cardiovascular-agents and Cardiomegaly

Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer's or Parkinson's disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.

Topics: Alzheimer Disease; Animals; Antineoplastic Agents; Apoptosis; Cardiomegaly; Cardiovascular Agents; Cell Cycle; Cyclin-Dependent Kinases; Cyclins; Gene Expression Regulation; Humans; Neoplasms; Neuroprotective Agents; Parkinson Disease; Protein Kinase Inhibitors; Saccharomyces cerevisiae; Stroke

A wide range of histone deacetylase (HDAC) inhibitors have been studied for their therapeutic potential because the excessive activity and expression of HDACs have been implicated in the pathogenesis of cardiac diseases. An increasing number of preclinical studies have demonstrated the cardioprotective effects of numerous HDAC inhibitors, suggesting a wide variety of mechanisms by which the inhibitors protect against cardiac stress, such as the suppression of cardiac fibrosis and fetal gene expression, enhancement of angiogenesis and mitochondrial biogenesis, prevention of electrical remodeling, and regulation of apoptosis, autophagy, and cell cycle arrest. For the development of isoform-selective HDAC inhibitors with high efficacy and low toxicity, it is important to identify and understand the mechanisms responsible for the effects of the inhibitors. This review highlights the preclinical effects of HDAC inhibitors that act against Zn

Topics: Animals; Antihypertensive Agents; Atrial Fibrillation; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Fibrosis; Heart Rate; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hypertension; Myocardial Infarction; Myocardium; Signal Transduction; Ventricular Remodeling

The underlying cause of cardiac hypertrophy, fibrosis, and heart failure has been investigated in great detail using different mouse models. These studies indicated that cGMP and cGMP-dependent protein kinase type I (cGKI) may ameliorate these negative phenotypes in the adult heart. Recently, evidence has been published that cardiac mitochondrial BKCa channels are a target for cGKI and that activation of mitoBKCa channels may cause some of the positive effects of conditioning in ischemia/reperfusion injury. It will be pointed out that most studies could not present convincing evidence that it is the cGMP level and the activity cGKI in specific cardiac cells that reduces hypertrophy or heart failure. However, anti-fibrotic compounds stimulating nitric oxide-sensitive guanylyl cyclase may be an upcoming therapy for abnormal cardiac remodeling.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Fibrosis; Heart Failure; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Second Messenger Systems; Ventricular Remodeling

Heart failure is a major medical and economic burden throughout the world. Although various treatment options are available to treat heart failure, death rates in both men and women remain high. Potential adjunctive therapies may lie with use of herbal medications, many of which possess potent pharmacological properties. Among the most widely studied is ginseng, a member of the genus Panax that is grown in many parts of the world and that has been used as a medical treatment for a variety of conditions for thousands of years, particularly in Asian societies. There are a number of ginseng species, each possessing distinct pharmacological effects due primarily to differences in their bioactive components including saponin ginsenosides and polysaccharides. While experimental evidence for salutary effects of ginseng on heart failure is robust, clinical evidence is less so, primarily due to a paucity of large-scale well-controlled clinical trials. However, there is evidence from small trials that ginseng-containing Chinese medications such as Shenmai can offer benefit when administered as adjunctive therapy to heart failure patients. Substantial additional studies are required, particularly in the clinical arena, to provide evidence for a favourable effect of ginseng in heart failure patients.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Clinical Trials as Topic; Disease Models, Animal; Ginsenosides; Heart Failure; Humans; Panax; Phytotherapy; Plant Extracts; Plants, Medicinal; Treatment Outcome

The incidence, prevalence, and hospitalization rates associated with cardiovascular diseases (CVDs) are projected to increase substantially in the world. Understanding of the biological and pathophysiological mechanisms of survival can help the researchers to develop new management modalities. Numerous experimental studies have demonstrated that mid-chain HETEs are strongly involved in the pathogenesis of the CVDs. Mid-chain HETEs are biologically active eicosanoids that result from the metabolism of arachidonic acid (AA) by both lipoxygenase and CYP1B1 (lipoxygenase-like reaction). Therefore, identifying the localizations and expressions of the lipoxygenase and CYP1B1 and their associated AA metabolites in the cardiovascular system is of major importance in understanding their pathological roles. Generally, the expression of these enzymes is shown to be induced during several CVDs, including hypertension and cardiac hypertrophy. The induction of these enzymes is associated with the generation of mid-chain HETEs and subsequently causation of cardiovascular events. Of interest, inhibiting the formation of mid-chain HETEs has been reported to confer a protection against different cardiac hypertrophy and hypertension models such as angiotensin II, Goldblatt, spontaneously hypertensive rat and deoxycorticosterone acetate (DOCA)-salt-induced models. Although the exact mechanisms of mid-chain HETEs-mediated cardiovascular dysfunction are not fully understood, the present review proposes several mechanisms which include activating G-protein-coupled receptor, protein kinase C, mitogen-activated protein kinases, and nuclear factor kappa B. This review provides a clear understanding of the role of mid-chain HETEs in the pathogenesis of cardiovascular diseases and their importance as novel targets in the treatment for hypertension and cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular System; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme Inhibitors; Drug Design; Humans; Hydroxyeicosatetraenoic Acids; Hypertension; Lipoxygenase; Lipoxygenase Inhibitors; Molecular Targeted Therapy; Signal Transduction

Mammalian target of rapamycin (mTOR) is an evolutionary conserved kinase that senses the nutrient and energy status of cells, the availability of growth factors, stress stimuli and other cellular and environmental cues. It responds by regulating a range of cellular processes related to metabolism and growth in accordance with the available resources and intracellular needs. mTOR has distinct functions depending on its assembly in the structurally distinct multiprotein complexes mTORC1 or mTORC2. Active mTORC1 enhances processes including glycolysis, protein, lipid and nucleotide biosynthesis, and it inhibits autophagy. Reported functions for mTORC2 after growth factor stimulation are very diverse, are tissue and cell-type specific, and include insulin-stimulated glucose transport and enhanced glycogen synthesis. In accordance with its cellular functions, mTOR has been demonstrated to regulate cardiac growth in response to pressure overload and is also known to regulate cells of the immune system. The present manuscript presents recently obtained insights into mechanisms whereby mTOR may change anabolic, catabolic and stress response pathways in cardiomocytes and discusses how mTOR may affect inflammatory cells in the heart during hemodynamic stress. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Humans; Inflammation Mediators; Myocarditis; Myocytes, Cardiac; Protein Biosynthesis; Protein Kinase Inhibitors; Proteolysis; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Remodeling

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a family of cation channels activated by hyperpolarized membrane potentials and stimulated by intracellular cyclic nucleotides. The four members of this family, HCN1-4, show distinct biophysical properties which are most evident in the kinetics of activation and deactivation, the sensitivity towards cyclic nucleotides and the modulation by tyrosine phosphorylation. The four isoforms are differentially expressed in various excitable tissues. This review will mainly focus on recent insights into the functional role of the channels apart from their classic role as pacemakers. The importance of HCN channels in the cardiac ventricle and ventricular hypertrophy will be discussed. In addition, their functional significance in the peripheral nervous system and nociception will be examined. The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues. Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions. This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

Topics: Action Potentials; Animals; Cardiomegaly; Cardiovascular Agents; Coronary Artery Disease; Cyclic Nucleotide-Gated Cation Channels; Heart Ventricles; Neurons; Protein Isoforms

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP450) products of arachidonic acid and EETs are endogenous lipid mediators synthesized by the vascular endothelium which perform important biological functions, including vasodilation, anti-inflammation, antimigratory, and cellular signaling regulations. However, EETs are rapidly degraded by soluble epoxide hydrolase (sEH) to the corresponding diols: dihydroxyeicosatrienoic acids (DHETs), which have little active in causing vasorelaxation. A number of studies have supported that the inhibition of sEH (sEHIs) had cardiovascular protective effects in hypertension, cardiac hypertrophy, atherosclerosis, ischemia-reperfusion injury, and ischemic stroke. Moreover, sEHIs could slow the progression of inflammation, protect end-organ damage and prevent ischemic events, also, attenuate endothelial dysfunction, suggesting that the pharmacological blockade of sEH might provide a broad and novel avenue for the treatment of many cardiovascular diseases.

Topics: Animals; Brain Ischemia; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; Polymorphism, Genetic; Reperfusion Injury; Risk; Stroke

The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels - or perhaps distinct forms of autophagic flux - contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''

Topics: Adenylate Kinase; Animals; Autophagy; Cardiomegaly; Cardiovascular Agents; Chromatin Assembly and Disassembly; Cyclic AMP-Dependent Protein Kinases; Heart Failure; Histone Acetyltransferases; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Inositol 1,4,5-Trisphosphate Receptors; Mechanistic Target of Rapamycin Complex 1; Molecular Targeted Therapy; Multiprotein Complexes; Myocardium; Proteins; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Cardiac hypertrophy develops most commonly in response to hypertension and is an independent risk factor for the development of heart failure. The mechanisms by which cardiac hypertrophy may be reversed to reduce this risk have not been fully determined to the point where mechanism-specific therapies have been developed. Recently, proteases in the calpain family have been implicated in the regulation of the development of cardiac hypertrophy in preclinical animal models. In this review, we summarize the molecular mechanisms by which calpain inhibition has been shown to modulate the development of cardiac (specifically ventricular) hypertrophy. The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed.

Topics: Animals; Calpain; Cardiomegaly; Cardiovascular Agents; Cysteine Proteinase Inhibitors; Disease Models, Animal; Drug Design; Heart Ventricles; Humans; Signal Transduction; Ventricular Remodeling

Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli. It enables myocytes to increase their work output, which improves cardiac pump function. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world. A number of signaling modulators that influence gene expression, apoptosis, cytokine release and growth factor signaling, etc. are known to regulate heart. By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed. This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy. In this review, we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin, cGMP, NFAT, natriuretic peptides, histone deacetylase, IL-6 cytokine family, Gq/G11 signaling, PI3K, MAPK pathways, Na/H exchanger, RAS, polypeptide growth factors, ANP, NO, TNF-alpha, PPAR and JAK/STAT pathway, microRNA, Cardiac angiogenesis and gene mutations in adult heart. Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy. The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy, with special emphasis on novel researches and investigations.

Topics: Cardiomegaly; Cardiovascular Agents; Drug Delivery Systems; Genetic Variation; Heart Failure; Humans; Models, Biological; Myocytes, Cardiac; Neovascularization, Physiologic; Signal Transduction

A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential beneficial effects were demonstrated in experimental models of congestive heart failure and left ventricular hypertrophy. Some of the observed effects resemble the basic mechanisms of ischaemic pre-conditioning, mimicking both acute and delayed effects. Other effects may be due to action on systemic and cardiac haemodynamics. Mechanisms and signalling pathways, characterized in some of the experimental models, appear to be complex: for instance, the rate of cyclic guanosine monophosphate (cGMP) synthesis and the functional compartmentalization of intracellular cGMP metabolism as well as interaction with ss-adrenergic and nitric oxide signalling may influence effects in different experimental settings. In this review, we discuss mechanisms, signalling pathways, and experimental limitations and touch on considerations for translation into potentially useful applications in the clinical arena.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

The circadian system has been shown to be fundamentally important in human health and disease. Recently, there have been major advances in our understanding of daily rhythmicity, and its relevance to human physiology, and to the pathogenesis and treatment of cardiac hypertrophy and heart failure. Cardiovascular tissues, such as heart and blood vessels, show remarkable daily variation in gene expression, metabolism, growth, and remodeling. Moreover, synchrony of daily molecular and physiological rhythms is integral to healthy organ growth and renewal. Disruption of these rhythms adversely affects normal growth, also the remodeling mechanisms in disease, leading to gross abnormalities in heart and vessels. These observations provide new insights into the pathogenesis, diagnosis, treatment, and prevention of heart disease. In this review, we focus on the recent advances in circadian biology and cardiovascular function, with particular emphasis on how this applies to human myocardial hypertrophy and heart failure, and the implications and importance for translational medicine.

Topics: Animals; Biological Clocks; Cardiomegaly; Cardiovascular Agents; Cardiovascular System; Chronobiology Disorders; Circadian Rhythm; Drug Chronotherapy; Gene Expression Regulation; Heart Failure; Humans; Sleep; Treatment Outcome

There has been growing interest in targeting myocardial substrate metabolism for the therapy of cardiovascular and metabolic diseases. This is largely based on the observation that cardiac metabolism undergoes significant changes during both physiologic and pathologic stresses. In search for an effective therapeutic strategy, recent studies have focused on the functional significance of the substrate switch in the heart during stress conditions, such as cardiac hypertrophy and failure, using both pharmacologic and genetic approaches. The results of these studies indicate that both the capacity and the flexibility of the cardiac metabolic network are essential for normal function; thus, their maintenance should be the primary goal for future metabolic therapy.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Energy Metabolism; Fatty Acids; Genetic Therapy; Genotype; Heart Failure; Humans; Myocytes, Cardiac; Phenotype

The renin-angiotensin system, traditionally viewed as a circulatory system, has significantly expanded in the last two decades to include independently regulated local systems in several tissues, newly identified active products of angiotensin II, and new receptors and functions of renin-angiotensin system components. In spite of our increased understanding of the renin-angiotensin system, a role of angiotensin II in cardiac hypertrophy, through direct effects on cardiovascular tissue, is still being debated. Here, we address the cardiovascular effects of angiotensin II and the role an intracellular renin-angiotensin system might play.. Recent studies have shown that cardiac myocytes, fibroblasts and vascular smooth muscle cells synthesize angiotensin II intracellularly. Some conditions, such as high glucose, selectively increase intracellular generation and translocation of angiotensin II to the nucleus. Intracellular angiotensin II regulates the expression of angiotensinogen and renin, generating a feedback loop. The first reaction of intracellular angiotensin II synthesis is catalyzed by renin or cathepsin D, depending on the cell type, and chymase, not angiotensin-converting enzyme, catalyzes the second step.. These studies suggest that the intracellular renin-angiotensin system is an important component of the local system. Alternative mechanisms of angiotensin II synthesis and action suggest a need for novel therapeutic agents to block the intracellular renin-angiotensin system.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Extracellular Fluid; Fibrosis; Humans; Intracellular Fluid; Myocardium; Renin-Angiotensin System; Signal Transduction; Ventricular Remodeling

This paper will review the role of the sympathetic nervous system in the pathogenesis of the metabolic syndrome as well as its importance as target of non-pharmacologic and pharmacologic treatment.. Several indices of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals and efferent postganglionic muscle sympathetic nerve traffic, have all shown an increase in the different conditions clustering in metabolic syndrome, such as obesity, hypertension and insulin resistance state. This increase: 1) appears to be potentiated in the metabolic syndrome; and 2) contributes to a large extent at the cardiovascular structural and functional alterations typical of the disease. Based on this evidence, non-pharmacologic life-style interventions as well as drug treatment procedures used in the therapeutic approach to the metabolic syndrome should be aimed at exerting not only favourable haemodynamic and metabolic effects but also pronounced sympathoinhibition.. The data reviewed in this paper strongly support the relevance of the sympathetic nervous system in the pathogenesis of the metabolic syndrome and the importance of the sympathomodulation as a specific aim of therapeutic intervention.

Topics: Adrenergic Fibers; Blood Pressure; Blood Vessels; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Health Behavior; Humans; Hypertension; Life Style; Metabolic Syndrome; Obesity; Risk Factors; Sympathetic Nervous System

The phospholipases associated with the cardiac sarcolemmal (SL) membrane hydrolyze specific membrane phospholipids to generate important lipid signaling molecules, which are known to influence normal cardiac function. However, impairment of the phospholipases and their related signaling events may be contributory factors in altering cardiac function of the diseased myocardium. The identification of the changes in such signaling systems as well as understanding the contribution of phospholipid-signaling pathways to the pathophysiology of heart disease are rapidly emerging areas of research in this field. In this paper, I provide an overview of the role of phospholipid-mediated signal transduction processes in cardiac hypertrophy and congestive heart failure, diabetic cardiomyopathy, as well as in ischemia-reperfusion. From the cumulative evidence presented, it is suggested that phospholipid-mediated signal transduction processes could serve as novel targets for the treatment of the different types of heart disease.

Topics: Animals; Cardiomegaly; Cardiomyopathies; Cardiovascular Agents; Diabetes Complications; Enzyme Inhibitors; Heart Diseases; Heart Failure; Humans; Myocardial Reperfusion Injury; Myocardium; Phospholipases; Phospholipids; Sarcolemma; Signal Transduction

Pathological stress from cardiovascular disease stimulates hypertrophy of heart cells, which increases the risk of cardiac morbidity and mortality. Recent evidence has indicated that inhibiting such hypertrophy could be beneficial, encouraging drug discovery and development efforts for agents that could achieve this goal. Most existing therapies that have antihypertrophic effects target outside-in signalling in cardiac cells, but their effectiveness seems limited, and so attention has recently turned to the potential of targeting intracellular signalling pathways. Here, we focus on new developments with small-molecule inhibitors of cardiac hypertrophy, summarizing both agents that have been in or are poised for clinical testing, and pathways that offer further promising potential therapeutic targets.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amides; Animals; Cardiomegaly; Cardiovascular Agents; Humans; Models, Biological; Molecular Structure; Pyridines; Receptors, Cell Surface; Signal Transduction

Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic heart failure (HF) by influencing heart contractility, inducing hypertrophy and promoting apoptosis, contributing to myocardial remodeling. While several stimuli may be operating such as heat shock proteins, microbial antigens and oxidative stress, it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in HF regardless of the initial event. Traditional cardiovascular drugs appear to have little influence on the cytokine network, and immunomodulatory therapy has emerged as a possible new treatment modality in HF. Several animal studies and also some clinical studies have suggested that downregulation of inflammation may improve cardiac performance. However, the results from the placebo-controlled anti-tumor necrosis factor studies suggest no improvement or even adverse effects of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients resulting in beneficial net effects. Further research will have to identify more precisely the most important actors in the immunopathogenesis of chronic HF in order to develop more specific immunomodulating agents for this disorder.

Topics: Animals; Apoptosis; Cardiomegaly; Cardiovascular Agents; Chronic Disease; Clinical Trials as Topic; Cytokines; Down-Regulation; Heart Failure; Humans; Immunologic Factors; Inflammation; Myocardial Contraction; Treatment Outcome; Ventricular Remodeling

Cardiac hypertrophy occurs in response to long-term increases in haemodynamic load related to a variety of physiological and pathological conditions. Cardiac hypertrophy developing in pathological conditions with increased load often progresses to a decompensated stage with cardiac contractile dysfunction, clinical signs of heart failure and premature death. Cardiac hypertrophy associated with adverse outcomes is said to be maladaptive. Conversely, there are settings where cardiac hypertrophy appears to be purely adaptive (e.g., hypertrophy in response to regular physical exercise). In these circumstances, hypertrophy is associated with preserved contractile performance and a favourable prognosis. Cardiac myocyte hypertrophy is controlled by growth factor receptors and mechanical stress sensors which activate a complex network of signalling pathways. These pathways promote a multitude of qualitative and quantitative changes in gene expression levels in cardiomyocytes. Reprogramming of gene expression, much more than cardiac (myocyte) hypertrophy per se, ultimately determines if cardiac hypertrophy will be adaptive or maladaptive. Pharmacological modification of gene expression in the hypertrophied heart may, therefore, be an attractive approach to prevent or even treat maladaptive hypertrophy and heart failure. Calcineurin is a serine-threonine phosphatase that is activated by sustained increases in [Ca2+]i in cardiomyocytes. Although it has been firmly established that calcineurin plays a critical role in the development of cardiac hypertrophy, the question of whether calcineurin activation serves an adaptive or maladaptive role is still unresolved. An answer to this question is crucial if calcineurin is to be developed as a drug target. The authors propose that calcineurin acts as a double-edged sword; excessive activation of calcineurin is maladaptive, its activation at endogenous levels and at specific subcellular microdomains, however, promotes adaptation. Calcineurin itself may, therefore, not be a convenient target for drug development. However, because maladaptive hypertrophy is ultimately a transcriptional disorder, definition of the transcriptional programme activated by distinct calcineurin activation levels may permit identification of novel, attractive drug targets.

Topics: Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cardiovascular Agents; Heart Failure; Humans; Transcription, Genetic

Topics: Aged; Cardiomegaly; Cardiovascular Agents; Echocardiography; Female; Heart Failure; Humans; Hypertension; Practice Guidelines as Topic; Stroke Volume; Ventricular Dysfunction

Although the past number of years have seen a substantial improvement in the therapeutic approaches for the treatment of heart failure, mortality rates continue to be high. Moreover, the incidence of heart failure is expanding rapidly. Sodium-hydrogen exchange (NHE) is a key target for the treatment of heart failure. NHE is a major mechanism for intracellular pH regulation in most cell types, including the cardiac cell. Seven isoforms of NHE have been identified so far although cardiac cells possess primarily the ubiquitous NHE-1 subtype. NHE-1 is a major contributor to ischaemic and reperfusion injury and NHE-1 inhibitors exert marked cardioprotective effects, particularly when administered before ischaemia, findings which have now been extended to clinical trials. It is emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertropic factors such as angiotensin II, endothelin-1 and beta(1) adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Drug Design; Drug Evaluation, Preclinical; Gene Expression Regulation; Heart Failure; Humans; Hypertrophy, Left Ventricular; Ion Transport; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Sodium; Sodium-Hydrogen Exchangers; Ventricular Remodeling

Cardiotrophin-1 (CT-1) originally was discovered as a factor that can induce hypertrophy of cardiac myocytes, both in vitro and in vivo. Subsequently, CT-1 has been shown to have a wide variety of different effects on cardiac and noncardiac, cells including the ability to stimulate the survival of both cardiac and neuronal cells. Like other members of the interleukin-6 family of cytokines, CT-1 stimulates both the p42/p44 mitogen-activated protein kinase pathway and the Janus-activated kinase/signal transducers and activators of transcription pathway. Interestingly, whilst activation of the p42/p44 mitogen-activated protein kinase pathway is necessary for the survival-promoting effects of CT-1 in cardiac cells, it is not required for its hypertrophic effect, which is likely to involve activation of the Janus-activated kinase/signal transducer and activator of transcription-3 pathway. CT-1, therefore, may be of use as a novel cardioprotective agent, particularly if its hypertrophic effect can be specifically inhibited.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Clinical Trials as Topic; Cytokines; Heart; Humans; In Vitro Techniques; Signal Transduction; Tissue Distribution

Various proteins of cardiac myocytes are preprogrammed at a very early stage of heart development, but functional load (stretch, pressure) plays an important role in their expression under both physiological and pathological circumstances. Mechanical factors are also important in growth of vessels, particularly with respect to hypertrophy or hyperplasia of vascular smooth muscle. Their effect on growth of endothelial cells is less clear. Although they have been studied in cell culture, little is known about their involvement in capillary growth in vivo. Their possible role is considered in capillary growth in the normal adult heart where it was elicited by long-term administration of various vasodilators, by long-term bradycardia, or by increased inotropic action. Here the mechanical stimuli may act either by increased shear stress (resulting from increased velocity of flow in long-term dilatation) or by increasing vessel wall tension (in conjunction with increased diameters and/or stretch produced by increased inotropism). While the role of growth factors in the development of myocytes has been established, it is still questionable in capillary growth. It is also possible that various growth factors exert their effect on vessel growth by their vasoactive activity.

Topics: Animals; Biomechanical Phenomena; Capillaries; Cardiomegaly; Cardiovascular Agents; Coronary Vessels; Growth Substances; Heart; Hemodynamics; Humans; Rabbits; Rats

To discuss the important predictors of ventricular enlargement after myocardial infarction and the appropriate time frame for the initiation of medical and pharmacologic therapy.. A review of the important contributions relative to the process known as "postinfarction ventricular remodeling" is provided; current clinical implications and areas for future investigation are discussed.. Ventricular dilatation is an important factor in the prognosis after infarction. Stretching and thinning of the myocardium within the infarct region can be seen within hours after the acute event and may be accompanied by delayed but potentially progressive stretching and thinning in the noninfarct regions. Development of left ventricular hypertrophy in the nonischemic myocardium, in response to increased wall stress, can be observed but may be insufficient for proper compensation. This process is referred to as postinfarction remodeling and can result in progressive and long-term changes in ventricular architecture and function in the absence of additional ischemic injury.. The most effective way to limit the extent of postinfarction ventricular remodeling is to limit infarct size by prompt medical intervention within the first few hours. In addition to traditional post-infarction medications such as beta-blockers, nitrates, and aspirin, long-term benefit may be derived by use of adjunctive pharmacologic therapy such as angiotensin converting enzyme inhibitors, which have been shown to be valuable in limiting the extent of ventricular chamber dilatation after infarction. Studies in animal models and conclusions from clinical trials have shown that angiotensin converting enzyme inhibitors also decrease late mortality and cardiac morbidity after infarction, likely through favorable effects on both hemodynamic and neurohumoral factors specific to this class of medication.. These investigations notwithstanding, further studies are necessary for a complete understanding of the pathogenesis of postinfarction ventricular remodeling and the appropriate timing of specific pharmacologic therapy intended to limit ventricular dilatation. The hemodynamic and neurohumoral interactions on and within the heart must be thoroughly understood relative to microscopic and macroscopic changes in cardiac size, shape, and function after myocardial infarction.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Heart Ventricles; Hemodynamics; Humans; Myocardial Infarction

Medical practice patterns change in response to a variety of stimuli, one of which may be the publication of the results of randomized clinical trials. We assessed the temporal association between the publication of clinical trials on myocardial infarction and changes in treatment practices for this disorder.. We analyzed the use of aspirin before and after myocardial infarction and that of calcium antagonists after myocardial infarction in 2231 survivors of myocardial infarction enrolled in the Survival and Ventricular Enlargement (SAVE) study over a three-year period (from January 1987 through January 1990). The proportion of patients using these treatments was analyzed before and after the publication dates of three clinical trials: the Physicians' Health Study, published in January 1988, which supported the use of aspirin to prevent a first myocardial infarction; the Second International Study of Infarct Survival (ISIS-2), published in August 1988, which supported the use of aspirin after myocardial infarction; and the Multicenter Diltiazem Postinfarction Trial, published in August 1988, which reported a deleterious effect of diltiazem in some patients after myocardial infarction.. The use of aspirin before myocardial infarction increased from 16.2 percent to 23.9 percent between January 1987 and January 1990 (P less than 0.001). Enrollment in the study after the publication of the Physicians' Health Study independently predicted aspirin use before myocardial infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85). The use of aspirin after myocardial infarction increased from 38.8 percent to 71.9 percent (P less than 0.001) during the three-year study period. Enrollment in the study after the publication of ISIS-2 independently predicted the use of aspirin after myocardial infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76). The use of calcium antagonists after myocardial infarction decreased from 57.1 percent to 33.1 percent (P less than 0.001) during the study period. Enrollment in the study after the publication of the Multicenter Diltiazem Postinfarction Trial independently predicted the use of calcium antagonists after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57).. These observations suggest that randomized clinical trials have a measurable influence on medical practice patterns.

Topics: Adult; Aged; Aspirin; Calcium Channel Blockers; Captopril; Cardiomegaly; Cardiovascular Agents; Diltiazem; Drug Utilization; Female; Humans; Male; Middle Aged; Myocardial Infarction; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Survival Rate; Time Factors; United States

Topics: Acute Disease; Bisoprolol; Cardiomegaly; Cardiomyopathies; Cardiovascular Agents; Echocardiography; Genetic Testing; Heart Failure; Humans; Loeys-Dietz Syndrome; Losartan; Male; Middle Aged; Mutation; Pulmonary Edema; Receptor, Transforming Growth Factor-beta Type I; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

The renin-angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3-7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3-7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3-7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3-7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3-7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3-7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3-7) could alleviate cardiac remodeling. The administration of Ang-(3-7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Fibrosis; Isoproterenol; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Ventricular Remodeling

Modified citrus pectin (MCP) is a specific inhibitor of galectin-3 (Gal-3) that is regarded as a new biomarker of cardiac hypertrophy, but its effect is unclear. The aim of this study is to investigate the role and mechanism of MCP in isoproterenol (ISO)-induced cardiac hypertrophy. Rats were injected with ISO to induce cardiac hypertrophy and treated with MCP. Cardiac function was detected by ECG and echocardiography. Pathomorphological changes were evaluated by the haematoxylin eosin (H&E) and wheat germ agglutinin (WGA) staining. The hypertrophy-related genes for atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC), and the associated signal molecules were analysed by qRT-PCR and western blotting. The results show that MCP prevented cardiac hypertrophy and ameliorated cardiac dysfunction and structural disorder. MCP also decreased the levels of ANP, BNP, and β-MHC and inhibited the expression of Gal-3 and Toll-like receptor 4 (TLR4). Additionally, MCP blocked the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), but it promoted the phosphorylation of p38. Thus, MCP prevented ISO-induced cardiac hypertrophy by activating p38 signalling and inhibiting the Gal-3/TLR4/JAK2/STAT3 pathway.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Galectin 3; Isoproterenol; Janus Kinase 2; Male; Myocytes, Cardiac; Myosin Heavy Chains; Natriuretic Peptide, Brain; p38 Mitogen-Activated Protein Kinases; Pectins; Phosphorylation; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 4; Ventricular Function, Left; Ventricular Remodeling

Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart's workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels.. By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo.. We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.. Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Case-Control Studies; Cell Communication; Disease Models, Animal; Disease Progression; Endothelial Cells; Fibroblasts; Gene Expression Profiling; Humans; Macrophages; Male; Mice, Inbred C57BL; Molecular Targeted Therapy; Myocytes, Cardiac; RNA-Seq; Signal Transduction; Single-Cell Analysis; Transcriptome; Ventricular Remodeling

Obesity-induced cardiomyopathy involves chronic and sustained inflammation. The toll-like receptor 4 (TLR4) signaling pathway can associate innate immunity with obesity. Myeloid differentiation primary response 88 (MyD88), an indispensable downstream adaptor molecule of TLR4, has been reported to mediate obesity complications. However, whether inhibition of MyD88 can mitigate obesity-induced heart injury remains unclear. LM8, a new MyD88 inhibitor, exhibits prominent anti-inflammatory activity in lipopolysaccharide-treated macrophages. In this study, the protective effects of LM8 on a high-fat diet (HFD)-induced heart injury were assessed in a mouse model of obesity. As suggested from the achieved results, LM8 treatment alleviated HFD-induced pathological and functional damages of the heart in mice. Meantime, the treatment of mice with LM8 could significantly inhibit myocardial hypertrophy, fibrosis, inflammatory cytokines expression, and inflammatory cell infiltration induced by HFD. Besides, LM8 administration inhibited the formation of MyD88/TLR4 complex, phosphorylation of ERK, and activation of nuclear factor-κB induced by HFD. According to the achieved results, MyD88 inhibitor LM8 ameliorated obesity-induced heart injury by inhibiting MyD88-ERK/nuclear factor-κB dependent cardiac inflammatory pathways. Furthermore, targeting MyD88 might be a candidate of a therapeutic method to treat obesity-induced heart injury.

Topics: Animals; Cardiomegaly; Cardiomyopathies; Cardiovascular Agents; Cells, Cultured; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Male; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Myocarditis; Myocytes, Cardiac; NF-kappa B; Obesity; Signal Transduction; Toll-Like Receptor 4

Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, cilengitide, here used at low doses. Cilengitide targets αvβ3 integrin and this protein is upregulated in human dilated and ischaemic cardiomyopathies. Treatment of mice after abdominal aortic constriction (AAC) surgery with low-dose cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with an associated reduction in disease severity. At a molecular level, ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles, with a significant enhancement of pro-angiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment. Moreover, ldCil treatment of Angiotensin II-stimulated AngII-stimulated cardiomyocytes significantly restores transcriptomic profiles similar to those found in normal human heart. The significance of this finding is enhanced by transcriptional similarities between AngII-treated cardiomyocytes and failing human hearts. Taken together, our data provide evidence supporting a possible new strategy for improved heart failure treatment using low-dose RGD-mimetics with relevance to human disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Drug Repositioning; Fibrosis; Gene Expression Regulation; Heart Failure; Humans; Integrin alphaVbeta3; Male; Mice; Myocytes, Cardiac; Neovascularization, Physiologic; Recovery of Function; Signal Transduction; Snake Venoms; Transcriptome

Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca. Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload-induced cardiac hypertrophy and systolic and diastolic function by restoring Na

Topics: Animals; Calcium; Cardiomegaly; Cardiovascular Agents; Cell Line; Fibrosis; Heart Failure; Hypertension; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Random Allocation; Ranolazine; Sodium

Although many studies have reported the effects of AT1 receptor on dietary salt overload, the role of AT2 receptor in this model is far from completely elucidated. The present study aimed to better understand the role of AT2 receptor in cardiac structure alterations in response to chronic high salt intake in rats.. Male Wistar rats were fed a normal or high salt diet from weaning until 18 weeks of age. Both groups were subdivided into two groups. Starting at 7 weeks of age, rats were treated with or without compound 21 (0.3 mg/kg/day, n = 16), an AT2 receptor agonist. Metabolics and structural parameters were measured. BP, transverse cardiomyocyte and intersticial fibrose was higher in animals fed with high salt diet compared with normal salt fed animals.. Compound 21 prevented the development of cardiac hypertrophy and fibrosis, reduced the increase in blood pressure and prevented the lower weight gain in animals fed a high salt diet.

Topics: Animals; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Fibrosis; Hypertension; Male; Myocytes, Cardiac; Rats, Wistar; Receptor, Angiotensin, Type 2; Signal Transduction; Sodium Chloride, Dietary; Sulfonamides; Thiophenes; Ventricular Remodeling; Weight Gain

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Topics: Animals; Calcineurin; Cardiomegaly; Cardiovascular Agents; Dexamethasone; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Heart Ventricles; Hemodynamics; Macrophages; Male; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Ventricular Dysfunction; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

We investigated the underlying mechanism of ivabradine (IVA) in promoting angiogenesis and reducing cardiac hypertrophy in mice with myocardial infarction (MI).. Nineteen mice were randomly assigned into three groups as follows: sham group (10 ml/kg/day phosphate buffer saline (PBS), n=6), model group (MI and 10 ml/kg/day PBS, n=6) and IVA group (MI and 10 mg/kg/day IVA, n=7). All groups received an intragastric gavage for four weeks. Heart and body mass were measured. Cardiac function and heart rate were assessed by echocardiography and electrocardiography, respectively. The collagen deposition, area of cardiomyocytes, and number of capillaries were evaluated using Masson's staining, anti-wheat germ agglutinin (WGA) staining, and platelet endothelial cell adhesion molecule-1 (CD31) staining, respectively. The protein kinase B (Akt)- endothelial nitric oxide synthase (eNOS) signaling and p-38 mitogen-activated protein kinase (MAPK) family in myocardium were determined by western blot.. IVA treatment greatly improved cardiac dysfunction and suppressed cardiac hypertrophy at 4 weeks after MI (p<0.05). Heart rate and fibrotic area of IVA group declined notably compared to those of the model group (p<0.05). IVA administration substantially reduced cardiomyocyte size and increased capillary formation (p<0.05). Besides, IVA medication can enhance Akt-eNOS signaling and inhibit p38 MAPK phosphorylation in the heart of mice with MI (p<0.05).. IVA can perform two functions, the promotion of angiogenesis and the reduction of cardiac hypertrophy, both of which were closely associated with Akt-eNOS signaling activation and p38 MAPK inhibition.

Topics: Administration, Oral; Angiogenesis Inducing Agents; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Echocardiography; Electrocardiography; Heart Rate; Ivabradine; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Nitric Oxide Synthase Type III; Random Allocation

The effects of diazoxide on cardiac hypertrophy and miR-132 expression were characterized in adult rats and in cardiomyocytes. Diazoxide effects on reactive oxygen species (ROS) production and on the cAMP-response element binding (CREB) transcription factor's abundance in cardiomyocytes were also analyzed. ROS measurements used a fluorescent dye. Western blot analysis and quantitative Reverse Transcription Polymerase Chain Reaction were used to measure phosphorylated form of CREB (pCREB) abundance and miR-132 expression, respectively.. Isoproterenol (ISO) induced cardiac hypertrophy, an effect that was mitigated by diazoxide. The rate of ROS production, CREB phosphorylation, and miR-132 expression increased after the addition of ISO. H2O2 increased pCREB abundance and miR-132 expression; upregulation of miR-132 was blocked by the specific inhibitor of CREB transcription, 666-15. Consistent with a role of ROS on miR-132 expression, diazoxide prevented the increase in ROS production, miR-132 expression, and pCREB abundance produced by ISO. Phosphorylation of CREB by ISO was prevented by U0126, an inhibitor of mitogen-activated protein kinase.. Our data first demonstrate that diazoxide mitigates hypertrophy by preventing an increase in miR-132 expression. The mechanism likely involves less ROS production leading to less phosphorylation of CREB. Our data further show that ROS enhance miR-132 transcription, and that ISO effects are probably mediated by the mitogen-activated protein kinase pathway.

Topics: Animals; Animals, Newborn; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Diazoxide; Disease Models, Animal; Isoproterenol; Male; MicroRNAs; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Rats, Wistar; Reactive Oxygen Species; Signal Transduction

Peripartum cardiomyopathy (PPCM) is a systolic left ventricular dysfunction developing in the peripartum phase in previously healthy women. Relaxin-2 is a pregnancy hormone with potential beneficial effects in heart failure patients. We evaluated Relaxin-2 as a potential diagnostic marker and/or a therapeutic agent in PPCM.. In healthy peripartum women, serum Relaxin-2 levels (measured by ELISA in the second half of pregnancy) were elevated showing a decreasing trend in the first postpartum week and returned to non-pregnant levels thereafter. In PPCM patients diagnosed in the first postpartum week, serum Relaxin-2 levels were lower compared to healthy postpartum stage-matched controls. In PPCM patients diagnosed later (0.5-10 months postpartum) Relaxin-2 levels were in the range of non-pregnant controls and not different from healthy postpartum stage-matched controls. In mice, serum Relaxin-1 (functional equivalent of human Relaxin-2) was increased late in pregnancy and rapidly cleared in the first postpartum week. In mice with PPCM due to a cardiomyocyte-specific knockout of STAT3 (CKO) neither low nor high dose of recombinant Relaxin-2 (serelaxin, sRlx-LD: 30 µg/kg/day; sRlx-HD: 300 µg/kg/day) affected cardiac fibrosis, inflammation and heart failure but sRlx-HD increased capillary/cardiomyocyte ratio. sRlx-HD significantly increased heart/body weight ratio and cardiomyocyte cross-sectional area in postpartum CKO and wild-type mice without changing the foetal gene expression program (ANP or β-MHC). sRlx-HD augmented plasma Prolactin levels in both genotypes, which induced cardiac activation of STAT5. In vitro analyses showed that Prolactin induces cardiomyocyte hypertrophy via activation of STAT5.. Although Relaxin-2 levels seemed lower in PPCM patients diagnosed early postpartum, we observed a high pregnancy-related variance of serum Relaxin-2 levels peripartum making it unsuitable as a biomarker for this condition. Supplementation with sRlx may contribute to angiogenesis and compensatory hypertrophy in the diseased heart, but the effects are not sufficient to prevent heart failure in an experimental PPCM model.

Topics: Adult; Animals; Biomarkers; Cardiomegaly; Cardiomyopathies; Cardiovascular Agents; Case-Control Studies; Disease Models, Animal; Female; Heart Failure; Humans; Mice, Knockout; Myocytes, Cardiac; Postpartum Period; Pregnancy; Prolactin; Rats; Recombinant Proteins; Registries; Relaxin; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Stroke Volume; Ventricular Function, Left

The study aimed to investigate the protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats (SHRs) through the Cys-C/Wnt signaling pathway. Thirty SHRs were randomly divided into cardiac hypertrophy, low- and high-dose tanshinone IIA groups. Ten Wistar-Kyoto rats were selected as control group. The systolic blood pressure (SBP), heart weight (HW), left ventricular weight (LVW) and body weight (BW) of all rats were recorded. HE staining and qRT-PCR were applied to observe the morphology of myocardial tissue and mRNA expressions of COL1A1 and COL3A1. ELISA and Western blotting were used to measure the serum asymmetric dimethylarginine (ADMA), nitric oxide (NO) and cardiac troponin I (cTnI) levels, and the expressions of the Cys-C/Wnt signaling pathway-related proteins, eNOS and Nox4. Compared with the cardiac hypertrophy group, the SBP, HW/BW, LVW/BW, swelling degree of myocardial cells, COL1A1 and COL3A1 mRNA expressions, serum cTnI and ADMA levels, and the Cys-C/Wnt signaling pathway-related proteins and Nox4 expressions in the low- and high-dose tanshinone IIA groups were decreased, but the endothelial NO synthase (eNOS), phosphorylated eNOS (Ser1177) and NO expressions were increased. No significant difference was found between the low- and high-dose tanshinone IIA groups. Our study indicated a protective effect of tanshinone IIA against cardiac hypertrophy in SHRs through inhibiting the Cys-C/Wnt signaling pathway.

Topics: Abietanes; Animals; Arginine; Cardiomegaly; Cardiovascular Agents; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Cystatin C; Disease Models, Animal; Hypertension; Male; Myocardium; NADPH Oxidase 4; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Troponin I; Wnt Signaling Pathway

Andrographis paniculata (Burm. f.) Nees (Acanthaceae) has a considerable medicinal reputation in most parts of Asia as a potent medicine in the treatment of Endocrine disorders, inflammation and hypertension.. Water extract of A. paniculata and its active constituent andrographolide are known to possess anti-inflammatory and anti-apoptotic effects. Our aim is to identify whether A. paniculata extract could protect myocardial damage in high-fat diet induced obese mice.. The test mice were divided into three groups fed either with normal chow or with high fat diet (obese) or with high fat diet treated with A. paniculata extract (2g/kg/day, through gavage, for a week).. We found that the myocardial inflammation pathway related proteins were increased in the obese mouse which potentially contributes to cardiac hypertrophy and myocardial apoptosis. But feeding with A. paniculata extract showed significant inhibition on the effects of high fat diet.. Our study strongly suggests that supplementation of A. paniculata extract can be used for prevention and treatment of cardiovascular disease in obese patients.

Topics: Andrographis; Animals; Anti-Inflammatory Agents; Apoptosis; Cardiomegaly; Cardiovascular Agents; Collagen; Cyclooxygenase 2; Diet, High-Fat; Disease Models, Animal; Inflammation Mediators; Mice, Inbred C57BL; Myocytes, Cardiac; Obesity; Phytotherapy; Plant Extracts; Plants, Medicinal; Receptor, IGF Type 1; Signal Transduction; Solvents; Water

Inflammatory responses mediate the development of perivascular fibrosis and heart dysfunction induced by hypertension. Complement is an important inflammatory system, and we aimed to evaluate the effect of a specific C5a receptor antagonist (C5aRA), PMX53, on inflammation and perivascular fibrosis in the hypertensive heart of the mouse.. Hypertension was induced by angiotensin II (Ang II) subcutaneously infused at a dose of 1500 ng/kg/min for 7 days. PMX53 was administrated at a dose of 1mg/kg, intraperitoneally 1 day before and daily during Ang II infusion.. Although C5aRA treatment did not affect the elevated blood pressure by Ang II infusion, it reduced cardiomyocyte hypertrophy, cardiac inflammation, and perivascular fibrosis. The mRNA and protein levels of the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF), as measured by real-time polymerase chain reaction and immunohistochemistry staining, were also attenuated by C5aRA treatment after Ang II infusion.. Our data suggest that inhibition of C5aR could be a potential therapeutic strategy in preventing organ damage in Ang II-induced hypertension.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Collagen; Connective Tissue Growth Factor; Cytokines; Disease Models, Animal; Fibrosis; Hypertension; Mice, Inbred C57BL; Myocardium; Peptides, Cyclic; Receptor, Anaphylatoxin C5a; RNA, Messenger; Time Factors; Transforming Growth Factor beta1; Ventricular Remodeling

Nitroxyl (HNO) is a redox congener of NO. We now directly compare the antihypertrophic efficacy of HNO and NO donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting. Isopropylamine-NONOate (IPA-NO) elicited concentration-dependent inhibition of endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by l-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target soluble guanylyl cyclase (sGC)] but were unaffected by carboxy-PTIO (NO scavenger) or CGRP8-37 (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an l-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO release. IPA-NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO donor diethylamine-NONOate (DEA-NO) reproduced these IPA-NO actions but was sensitive to carboxy-PTIO rather than l-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that IPA-NO protection against cardiomyocyte hypertrophy is independent of both NO and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits hypertrophy independently of NO, even under conditions of elevated superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of cardiac hypertrophy, as stand-alone and/or add-on therapy to standard care.

Topics: Animals; Animals, Newborn; Antioxidants; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Gene Expression Regulation; Guanylate Cyclase; Hydrazines; Myocytes, Cardiac; Nitric Oxide Donors; Nitrogen Oxides; Pyrogallol; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Second Messenger Systems; Soluble Guanylyl Cyclase; Time Factors

Cardiac hypertrophy occurs in response to increased workload, such as hypertension or valvular heart disease. Oxidative stress has been implicated in cardiac hypertrophy and in its transition to heart failure. This study was taken up with the objective to evaluate the role of oxidative stress in cardiomyoblast hypertrophy and its modulation by Desmodium gangeticum (DG) that has been traditionally used in Ayurveda, an Indian system of medicine. The methanolic root extract was analyzed for total phenolic content and tested for antioxidant potential. Hypertrophy was induced by exposing H9c2 cell line to β-adrenergic receptor agonist, isoproterenol (ISO), for 96 hours. Analyses of reactive oxygen species (ROS) generation, mitochondrial transmembrane potential ([INCREMENT]Ψm), and integrity of permeability transition were performed in ISO as well as Desmodium and ISO-cotreated cells. The results demonstrated potent free radical scavenging activity of DG. Cell line studies showed significant increase in ROS generation, dissipation of [INCREMENT]Ψm, and permeability transition pore opening in ISO-treated cells. Desmodium was found to attenuate ISO-induced hypertrophy by reduction of ROS generation, restoration of [INCREMENT]Ψm, and prevention of permeability transition pore opening. This study is the first documentation of the modulatory effect of DG on cardiac hypertrophy.

Topics: Adrenergic beta-Agonists; Animals; Antioxidants; Cardiomegaly; Cardiovascular Agents; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Fabaceae; Isoproterenol; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myoblasts, Cardiac; Oxidative Stress; Phenols; Plant Extracts; Rats; Reactive Oxygen Species; Time Factors

Vasopeptidase inhibition (VPI), a therapeutic strategy by dual inhibition of both ACE and neutral endopeptidase 24.11, has not shown a prognostic benefit over ACE inhibition in chronic severe heart failure (CHF). Nevertheless, the effects of early treatment by VPI on cardiac remodelling have not been well assessed. We analysed the effects of early chronic VPI (50 mg/kg/day Omapatrilat) on cardiac remodelling and neurohumoral function during the progression of rapid ventricular pacing-induced heart failure in rabbits (early left ventricular dysfunction [ELVD]: 10 days at 330 bpm, CHF: further 10 days at 360 bpm). VPI-treated animals (ELVD-VPI n = 6; CHF-VPI n = 8) and placebo treated animals (ELVD n = 6; CHF n = 7) were compared with control rabbits (CTRL n = 5). LV fractional shortening (FS) and enddiastolic diameter (LVEDD) were assessed by echocardiography (12 MHz probe). LV BNP- and LV IL-6 gene expression was analysed quantitatively by real time PCR. Neurohumoral function was assessed by ANP, cGMP, plasma renin activity (PRA) and Aldosterone. In ELVD, LVEDD and atrial mass were significantly increased (both p < 0.05). This increase was markedly attenuated by VPI (both p < 0.05 vs. placebo). CHF was associated with a further increase in atrial mass and an increase in LV mass (both p < 0.05), which was again attenuated by VPI (atrial mass, p < 0.05 vs. untreated). LV BNP mRNA was significantly increased in CHF (p < 0.05 vs. control), and chronic VPI completely abolished this increase in ELVD and significantly attenuated it in CHF (p < 0.05 vs. CHF-placebo). Beyond that, the increase of cGMP was augmented by chronic VPI (p < 0.05 vs. placebo in CHF) in heart failure and that of Aldosterone was attenuated (p < 0.05 vs. placebo in ELVD), whereas PRA was temporarily increased (p < 0.05 vs. placebo in ELVD). Combined inhibition of ACE and NEP by VPI significantly inhibits early cardiac remodelling and LV BNP gene expression. If initiated early enough, it may slow down cardiac remodelling and represents a promising therapeutic strategy in progressive heart failure.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Male; Natriuretic Peptide, Brain; Neprilysin; Pyridines; Rabbits; Renin; Renin-Angiotensin System; RNA, Messenger; Tachycardia; Thiazepines; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Apoptosis; Cardiomegaly; Cardiovascular Agents; Gene Expression Regulation; Heart; Heart Failure; Humans; Myocardium; Nitric Oxide

Stimulation of cardiac AMP-activated protein kinase (AMPK) has been demonstrated in both prohypertrophic and antihypertrophic settings, although the reasons for such discrepant results are not well understood. We determined how AMPK is regulated in response to phenylephrine-induced cardiomyocyte hypertrophy and assessed whether AMPK activity may be a factor underlying the antihypertrophic effect of adenosine receptor agonists. The role of AMPK in hypertrophic responses was determined by assessing the effect of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside on three hypertrophic indexes, including protein synthesis, cell surface area, and fetal gene expression. The changes in phosphorylation of the catalytic alpha-subunit of AMPK at two different sites, Thr(172) and Ser(485/491), in response to phenylephrine and adenosine receptor agonists were also examined. 5-Aminoimidazole-4-carboxyamide ribonucleoside completely abolished phenylephrine-induced increases in protein synthesis, cell surface area, and fetal gene expression. AMPK phosphorylation time course studies revealed that phenylephrine induced a time-dependent activation at site Ser(485/491), in contrast to adenosine receptor agonists, which demonstrated rapid AMPK phosphorylation at Thr(172). Furthermore, the phosphorylation at Ser(485/491) by phenylephrine was not affected by the addition of adenosine receptor agonists, although, conversely, phosphorylation of AMPK at Thr(172) by adenosine receptor agonists was abrogated by the addition of phenylephrine. We propose from these results that cardiomyocyte hypertrophic and antihypertrophic responses, at least with respect to inhibition of phenylephrine-induced hypertrophy by adenosine receptor agonists, are mediated by multisite AMPK regulation. The latter are reflected by increased phosphorylation at Ser(485/491) and at Thr(172), associated with prohypertrophic and antihypertrophic responses, respectively.

Topics: Adenosine; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Animals, Newborn; Blotting, Western; Cardiomegaly; Cardiotonic Agents; Cardiovascular Agents; Cell Size; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Heart Ventricles; Leucine; Myocytes, Cardiac; Phenylephrine; Phosphorylation; Rats; Rats, Sprague-Dawley; Ribonucleotides

We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.

Topics: Allyl Compounds; Animals; ATP-Binding Cassette Transporters; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epoprostenol; Heart Failure; Hypertension; In Vitro Techniques; KATP Channels; Male; Myocardium; Nitric Oxide; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Wistar; Receptors, Drug; Sulfonylurea Receptors; Tail; Vasodilator Agents; Ventricular Remodeling

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Heart; Humans; Kidney; Kidney Diseases; Mice; Myocardium; Rats; Renin-Angiotensin System; rho-Associated Kinases; Ventricular Remodeling

The nonpeptide AVE0991 is expected to be a putative new drug for cardiovascular diseases. However, the mechanisms for the cardioprotective actions of AVE0991 are still not fully understood. We planned to determine whether AVE0991 attenuates the angiotensin II (AngII)-induced myocardial hypertrophy and whether these AVE0991 effects involved transforming growth factor beta1 (TGF-beta1) and Smad2. A rat model of neonatal myocardial hypertrophy was induced by AngII. The AngII group significantly increased in protein content, surface area, and [(3)H]leucine incorporation efficiency by cardiomyocytes, compared to those of the control group (P < 0.01). The AngII group also had elevated TGF-beta1 and Smad2 expression (P < 0.01). These AngII-induced changes were significantly attenuated by AVE0991 in a dose-dependent manner. In our study, these actions of AngII (10(-6) mol/l) were significantly inhibited by both concentrations of AVE0991 (10(-5) mol/l and 10(-7) mol/l). Moreover, the high AVE0991 group had significantly better inhibition of myocardial hypertrophy than the low AVE0991 group. Meanwhile, the beneficial effects of AVE0991 were completely abolished when the cardiomyocytes were pretreated with Ang-(1-7) receptor antagonist A-779 (10(-6) mol/l). These results suggested that AVE0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-beta1/Smad2 signaling.

Topics: Angiotensin II; Animals; Animals, Newborn; Cardiomegaly; Cardiovascular Agents; Cell Size; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Imidazoles; Myocytes, Cardiac; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; RNA, Messenger; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta1

The furanocoumarin imperatorin has been reported to have hypotensive effect, and we have investigated its activity on myocardial hypertrophy. Imperatorin displayed similar chromatographic retention peak to verapamil in the model of cardiac muscle/cell membrane chromatography, and could reduce in a concentration-dependent way protein content and cell size of myocytes prestimulated with angiotensin II. The ratio of heart weight to body weight (mg/g) (4.13 ± 0.06 in SHRs, 3.77 ± 0.02 with imperatorin 25 mg kg(-1)d(-1) 16 17 ig, P<0.01) was significantly lower in the imperatorin-treated SHRs. Taken together, our observations show that imperatorin exerts anti-hypertrophic effect both in vitro and in vivo.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Furocoumarins; Heart Failure; Molecular Structure; Myocardium; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley

trans-Resveratrol (resveratrol) has been shown to have beneficial effects on the cardiovascular system in a number of studies. It is, however, unclear whether this naturally occurring compound can protect against cardiac hypertrophy. The aim of the present study was to investigate the effects of resveratrol on cardiac hypertrophy in vivo and the potential underlying mechanisms involving endothelin (ET), angiotensin (Ang) II and nitric oxide (NO) in partially nephrectomized rats. Animal models bearing cardiac hypertrophy were replicated in male Sprague-Dawley rats following partial nephrectomy (PNX). Resveratrol (10 or 50 mg/kg) was administered to rats by gavage for 4 weeks. Simultaneous PNX and sham operation controls were simultaneously established in the present study. The systolic blood pressure (SBP) of rats was measured at baseline and, along with heart weight, after 4 weeks treatment. Serum ET-1, AngII and NO concentrations were determined. In the present study, it was shown that, compared with rats in the sham-operated group, rats in the PNX group had significantly higher SBP (154.1 +/- 22.7 mmHg), heart weight (1.69 +/- 0.24 g) and serum ET-1 (125.70 +/- 26.27 pg/mL) and AngII serum concentrations (743.63 +/- 86.50 pg/mL), whereas serum NO concentrations were lower (21.1 +/- 6.9 micromol/L; all P < 0.05). These values in the sham control group were 114 +/- 10 mmHg, 1.28 +/- 0.13 g, 52.44 +/- 21.85 pg/mL, 528.7 +/- 158.5 pg/mL and 53.21 +/- 23.87 micromol/L, respectively. After 4 weeks treatment with 50 mg/kg resveratrol, SBP, heart weight and ET-1 and AngII concentrations had decreased to 135.4 +/- 15.8 mmHg, 1.39 +/- 0.15 g, 97.11 +/- 26.74 pg/mL and 629.64 +/- 116.18 pg/mL, respectively. However, the serum NO concentration had increased to 40.1 +/- 14.6 micromol/L. These values were significantly different from those obtained for the PNX group. In conclusion, trans-resveratrol appears to be able to protect against the increase in SBP and subsequent cardiac hypertrophy in vivo and the mechanisms responsible may involve, at least in part, modulation of NO, AngII and ET-1 production.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Endothelin-1; Hypertension, Renal; Male; Myocardium; Nephrectomy; Nitric Oxide; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

To investigate the effect of trans-resveratrol on hypertension-induced cardiac hypertrophy and its potential mechanisms involving endothelin (ET), angiotensin II (AngII) and nitric oxide (NO).. Animal models bearing cardiac hypertrophy were replicated in male SD rats following partially nephrectomy (PNX). 10 mg/kg bw or 50 mg/kg bw of resveratrol was administered to rats by gavage, respectively, for 4 weeks. PNX control and sham-operation control (SHAM) were simultaneously established. Systolic pressure of rats was measured through tail at baseline and it, as well as heart weight, was measured after 4-week treatment. Serum ET-1 and AngII concentrations were determined using radioimmunological assay and NO using nitric acid reductase method.. After 4-week treatment, animals in PNX control group had significantly higher systolic pressure and heart weight, higher ET-1 and AngII concentrations while lower NO concentrations, compared with those in SHAM group (P < 0.05). Rats treated with 50 mg/kg bw of resveratrol had significantly lower systolic pressure and heart weight, lower ET-1 concentrations while higher NO concentrations, compared with animals in PNX group (P < 0.05).. Trans-resveratrol could protect against the increase of systonic pressure and subsequent cardiac hypertrophy in vivo, which mechanisms might, at least partly, involve with its modulation on NO, AngII and ET.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Endothelin-1; Hypertension; Male; Myocardium; Nephrectomy; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. At weeks 20 and 24 the treadmill test was performed. YM598 prolonged running time, which had been shortened as a result of heart failure. The weights, relative to the body weight, of the left and right ventricles and lungs of surviving rats with CHF were significantly greater than those of sham-operated rats, suggesting hypertrophy of the ventricles and congestion of the lungs. Administration of YM598 markedly reduced ventricular hypertrophy and pulmonary congestion. Examination of cardiac function revealed that, in surviving CHF rats, the peak positive first derivative of left ventricular pressure was significantly lower, and left ventricular end-diastolic pressure, right ventricular systolic pressure and central venous pressure were significantly higher in comparison to sham-operated rats. These data demonstrate that, in rats with CHF, the contractile and diastolic capacity of the left ventricle decreased and pulmonary hypertension and systemic congestion occurred. Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.

Topics: Administration, Oral; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Endothelin A Receptor Antagonists; Exercise Tolerance; Fibrosis; Heart Failure; Hypertension, Pulmonary; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Physical Exertion; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Heart Failure; Humans; Myocardium; Signal Transduction; Transcription Factors

Heart failure (HF) is considered a putative factor predisposing to acute renal failure (ARF). Since outer medullary hypoxic injury may play an important role in the pathogenesis of acute tubular necrosis, we explored the impact of experimental HF on the propensity to develop ARF with hypoxic medullary injury following the inhibition of prostaglandin and nitric oxide synthesis.. Compensated, high-output HF was induced in Sprague-Dawley rats by aorto-caval fistula. At the eighth to ninth postoperative day, the rats were injected with indomethacin and N(omega) nitro-L-arginine methyl ester (L-NAME; ARF protocol) and were sacrificed 24 hours later for morphologic evaluation.. Kidney function comparably declined in HF-ARF rats and in control sham operated animals (CTR-ARF). Nevertheless, outer medullary hypoxic damage with medullary thick ascending limb (mTAL) necrosis occurred almost exclusively in the HF-ARF group (11 +/- 4% vs. 0.2 +/- 0.2% of tubules in CTR-ARF, P < 0.03). In a third group of HF animals subjected to vehicles only (HF-Nil), kidney function was preserved and renal morphology remained intact. Papillary-tip necrosis was consistently found in all animals subjected to indomethacin and L-NAME, irrespective of preconditioning. Morphometric evaluation disclosed that HF was not associated with mTAL hypertrophy.. Incipient HF predisposes to hypoxic outer medullary injury, probably reflecting the impact of regional vasoconstrictive stimuli rather than tubular hypertrophy when protective local vasodilating mechanisms are hampered. The presence and extent of outer medullary hypoxic damage cannot be predicted from the functional derangement, which in the experimental settings may also represent prerenal azotemia or papillary damage.

Topics: Acute Kidney Injury; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Enzyme Inhibitors; Heart Failure; Hypoxia; Indomethacin; Kidney Medulla; Kidney Tubular Necrosis, Acute; Loop of Henle; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Renal Circulation; Vasoconstriction; Vasodilation

We examined the effects of MET-88 on haemodynamics and cardiac hypertrophy in rats with an aortocaval shunt (A-V shunt). On the day of surgery, an A-V shunt was produced by using an 18-gauge needle in Wistar rats as described by Garcia and Diebold. MET-88 and captopril were orally administered to rats 1 week after surgery, and the administration was continued for 3 weeks. Four weeks after the surgery, A-V shunt-operated rats had biventricular hypertrophy and higher right atrial pressure (RAP) and left ventricular end-diastolic pressure (LVEDP) than sham-operated rats. Compared with untreated A-V shunt rats, those treated with MET-88 showed significant attenuation of the development of left ventricular (LV) hypertrophy and of the increased LVEDP. Captopril-treated A-V shunt rats also failed to show increases in LV weight and LVEDP. In in vitro studies, MET-88 had no effect on renin and angiotensin-converting enzyme (ACE) activities in the plasma of normal rats. These results suggest that MET-88 improved LV hypertrophy and LV dysfunction in rats with an A-V shunt. Furthermore, the data indicate that the beneficial effects of MET-88 may be attributed to some pathway, not involving the renin-angiotensin system, such as myocardial energy metabolism, venous return, etc. We conclude that MET-88 may be a novel agent for the therapy of chronic heart failure.

Topics: Animals; Body Weight; Cardiac Volume; Cardiomegaly; Cardiovascular Agents; Heart; Hemodynamics; Male; Methylhydrazines; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin; Ventricular Dysfunction, Left

A total of 502 patients presenting in Utsunomiya city and its suburbs during a 10-year period were studied to determine the clinical features of ischemic heart disease and to identify coronary risk factors. The male/female ratio was 1.21, but the ratio decreased with increasing age. The duration of chest pain showed a continuous spectrum between angina and infarction, with a short duration of chest pain not being useful for excluding the diagnosis of myocardial infarction. Hypertension was more common than hypercholesterolemia in this study, although the prevalence of the latter increased slightly with time, along with the shift towards a modernized occupational pattern. Smoking was a more important risk factor for ischemic heart disease in younger individuals than in the elderly, and diabetes mellitus was highly associated with the development of myocardial infarction. The incidence of radiologically diagnosed cardiac hypertrophy and aortic calcification decreased over time. These changes may have resulted in part from improved blood pressure control and the development of new anti-hypertensive and cholesterol-lowering agents.

Topics: Age Factors; Alcohol Drinking; Aortic Diseases; Arteriosclerosis; Calcinosis; Cardiomegaly; Cardiovascular Agents; Chest Pain; Comorbidity; Death, Sudden, Cardiac; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Japan; Male; Morbidity; Myocardial Ischemia; Occupations; Risk Factors; Smoking; Urban Population

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long-term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Cardiomegaly; Cardiovascular Agents; Cardiovascular Physiological Phenomena; Cardiovascular System; Hindlimb; Hypertension; Imidazoles; Losartan; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Time Factors

Diastolic dysfunction is characterized by an abnormal function of one or both ventricles which is manifested by an increased resistance to diastolic filling. The pathophysiology of diastolic dysfunction includes relaxation disturbances, abnormal diastolic filing and/or abnormal passive elastic properties. In 1/5 to 1/3 of all patients with congestive heart failure, diastolic dysfunction is found to be the sole cause of heart failure. The etiology is most commonly severe myocardial hypertrophy and less often coronary artery disease. The prognosis in patients with isolated diastolic dysfunction is good; the annual mortality rate is 8% and 5-year survival approximately 70%. Therapy is based on a reduction of circulating blood volume to reduce diastolic filling pressure and improvement of relaxation and diastolic filling by the administration of calcium antagonists.

Topics: Cardiomegaly; Cardiovascular Agents; Coronary Disease; Diastole; Heart Failure; Humans; Prognosis; Ventricular Function