natriuretic-peptide--c-type and Cardiovascular-Diseases

The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP, secreted by the heart, act as cardiac hormones, whereas CNP is an endothelial peptide. The aim of this manuscript is to review the production, action mechanisms, effects and clinical applications of natriuretic peptides.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Endocrine Glands; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides

Paracrine actions of CNP and rapid degradation at source severely limit study of CNP's many roles in vivo. However provided sensitive and validated assays are used, there is increasing evidence that low concentrations of bioactive CNP in plasma, and the readily detectable concentrations of the bio-inactive processed product of proCNP (aminoterminal proCNP), can be used to advance understanding of the hormone's role in pathophysiology. Provided renal function is normal, concordant changes in both CNP and NTproCNP reflect change in tissue production of proCNP whereas change in CNP alone results from altered rates of bioactive CNP degradation and are reflected in the ratio of NTproCNP to CNP. As already shown in juveniles, where plasma concentration of CNP products are higher and are associated with concurrent endochondral bone growth, measurements of plasma CNP products in mature adults have potential to clarify organ response to stress and injury. Excepting the role of CNP in fetal-maternal welfare, this review examines evidence linking plasma CNP products with function of a wide range of tissues in adults, including the impact of extraneous factors such as nutrients, hormone therapy and exercise.

Topics: Animals; Biomarkers; Bone Development; Cardiovascular Diseases; Fibrosis; Humans; Natriuretic Peptide, C-Type; Renal Insufficiency, Chronic

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Diseases; Diabetes Complications; Hepatitis; Humans; Hypertension; Kidney; Mice; Natriuretic Peptide, C-Type; Polymorphism, Genetic; Protein Precursors; Receptors, Atrial Natriuretic Factor; Renin-Angiotensin System; Sodium

The natriuretic peptide (NP) family includes atrial (ANP), brain or B-type (BNP) and C-type NP (CNP). A huge number of experimental and clinical studies, published in the 1st decade of this century, have added further support to the hypothesis that endocrine function in the human heart is a relevant component of a complex network including endocrine, nervous and immune systems. The NP hormones constitute a well-integrated regulatory system and share a similar spectrum of biological actions, although there are some differences in biological potency between ANP, BNP and CNP. However, several important issues on this field need to be investigated further. The production, secretion and peripheral degradation pathways of both BNP and CNP should be clarified in detail. In particular, the hypothesis that the circulating plasma pool of the prohormone can function as a precursor of the active peptide hormone should be demonstrated definitively. Recent findings indicate that peripheral processing of circulating prohormones could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening up new perspectives even in the treatment of heart failure. This hypothesis suggests a novel pharmacological target for drugs inducing and/or modulating the maturation of the prohormone into active hormone.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Heart; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides

Natriuretic peptide family consists of several hormones produced by cardiomyocyte, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). They possess similar gene structures and protective effects of cardiovascular physiology, such as anti-hypertrophy, anti-fibrosis, myocardial relaxation and blood pressure regulation. The corresponding natriuretic peptide receptor A, B and C mediate multiple effects of natriuretic peptides to maintain cardiovascular homeostasis. Specially, natriuretic peptide receptor-A preferentially binds ANP and BNP, while natriuretic peptide receptor-B is more selective for C-type natriuretic peptides. Natriuretic peptide receptor-C(NPR-C), binding all kinds of natriuretic peptides, clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation. BNP levels were reported to be a good predictor of left ventricular dysfunction and decompensated heart failure from a clinical standpoint. BNP infusion is an effective treatment for acute heart failure. Investigations on natriuretic peptides' single nucleotide polymorphisms and biological function suggested that they could be associated with several cardiovascular diseases, such as atrial fibrillation, cardiomyopathy, heart failure and so on. Transgenic mice with natriuretic peptides and their receptors gene deletion display myocardial hypertrophy and fibrosis, which are associated with the development of hypertension, cardiomyopathy and heart failure. Certain stimuli triggering cardiac hypertrophy and ischemic injuries may be involved in regulating gene expression of natriuretic peptides and their receptors. Therefore, advances in understanding of natriuretic peptide family genes and their regulatory mechanisms will lead to greater insight into the pathogenesis of cardiovascular diseases and blaze a new trail in clinical treatment.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides

The mammalian natriuretic peptide family consists of atrial (ANP), brain [B-type; BNP] and C-type natriuretic peptide (CNP) and three receptors, natriuretic receptors-A (NPR-A), -B (NPR-B) and -C (NPR-C). Both ANP and BNP are abundantly expressed in the heart and are secreted mainly from the atria and ventricles, respectively. By contrast, CNP is mainly expressed in the central nervous system, bone and vasculature. Plasma concentrations of both ANP and BNP are elevated in patients with cardiovascular disease, though the magnitude of the increase in BNP is usually greater than the increase in ANP. This makes BNP is a clinically useful diagnostic marker for several pathophysiological conditions, including heart failure, ventricular remodeling and pulmonary hypertension, among others. Recent studies have shown that in addition to BNP-32, proBNP-108 also circulates in human plasma and that levels of both forms are increased in heart failure. Furthermore, proBNP-108 is O-glycosylated and circulates at higher levels in patients with severe heart failure. In this review we discuss recent progress in our understanding of the biochemistry, molecular biology and clinical relevance of the natriuretic peptide system.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Gene Expression; Gene Expression Regulation; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Peptide Fragments; Tissue Distribution; Transcription, Genetic

In the last three decades many members of the natriuretic peptide family was isolated. The function and physiological role of these peptides are pleiotropic. All natriuretic peptides are synthesized from polypeptide precursors. Together with the sympathetic nervous system and other hormones they play key roles, like an endogenous system in the regulation of the body fluid homeostasis and blood pressure. Changes in this balance lead to dysfunction in the endothel and left ventricle, which can cause severe complications. In many cardiovascular diseases natriuretic peptides serve not only as marker for diagnosis and prognosis but they have therapeutic importance. In the last years the potential use of the elevated BNP levels for diagnosis of pre-eclampsia was examined. In our review we discuss the current understanding of molecular biology, biochemistry and clinical relevance of natriuretic peptides.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiovascular Diseases; Female; Humans; Liver Cirrhosis; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Pre-Eclampsia; Pregnancy; Renal Insufficiency; Shock, Septic; Tissue Distribution

C-type natriuretic peptide (CNP) is a member of the small family of natriuretic peptides that also includes atrial natriuretic peptide (ANP) and brain, or B-type natriuretic peptide (BNP). Unlike them, it performs its major functions in an autocrine or paracrine manner. Those functions, mediated through binding to the membrane guanylyl cyclase natriuretic peptide receptor B (NPR-B), or by signaling through the non-enzyme natriuretic peptide receptor C (NPR-C), include the regulation of endochondral ossification, reproduction, nervous system development, and the maintenance of cardiovascular health. To date, the regulation of CNP gene expression has not received the attention that has been paid to regulation of the ANP and BNP genes. CNP expression in vitro is regulated by TGF-β and receptor tyrosine kinase growth factors in a cell/tissue-specific and sometimes species-specific manner. Expression of CNP in vivo is altered in diseased organs and tissues, including atherosclerotic vessels, and the myocardium of failing hearts. Analysis of the human CNP gene has led to the identification of a number of regulatory sites in the proximal promoter, including a GC-rich region approximately 50 base pairs downstream of the Tata box, and shown to be a binding site for several putative regulatory proteins, including transforming growth factor clone 22 domain 1 (TSC22D1) and a serine threonine kinase (STK16). The purpose of this review is to summarize the current literature on the regulation of CNP expression, emphasizing in particular the putative regulatory elements in the CNP gene and the potential DNA-binding proteins that associate with them.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelial Cells; Gene Expression Regulation; Genome, Human; Humans; Myocytes, Smooth Muscle; Natriuretic Peptide, C-Type; Promoter Regions, Genetic; Regulatory Elements, Transcriptional; Repressor Proteins; RNA, Messenger; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

The natriuretic peptide (NP) family includes atrial natriuretic peptide (ANP), B-type natriuretic peptide, C-type natriuretic peptide and their receptors NPR-A, NPR-B and NPR-C. The effects exerted by this hormonal system in the control of cardiovascular, renal and endocrine functions have been extensively investigated. Moreover, the involvement of NP in the pathogenesis of cardiovascular diseases has been demonstrated. Among the NP components, NPR-C has been described, at the time of its discovery, as the clearance receptor of NP devoid of any physiological functions. Emerging roles of NPR-C, however, have been highlighted over the last few years in relation to its effects on the cardiovascular system and other organs. These effects appear to be directly mediated through distinct cAMP-dependent intracellular mechanisms. Moreover, evidence has been accumulated on a potential pathophysiological role of NPR-C in human diseases. Ongoing studies from our group are revealing its involvement in the mediation of antiproliferative effects exerted on vascular cells by a molecular variant of human ANP. Thus, a new appraisal of NPR-C is overcoming the traditional view of a mere clearance receptor. This review focuses on the most important evidence supporting an involvement of NPR-C in mediating some of the actions of NP and its direct implication in cardiovascular diseases. The current state of knowledge highlights the need of further studies to better clarify the specific roles of NPR-C in pathophysiological processes.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Peptide, C-Type; Obesity; Phenotype

Natriuretic peptides play a fundamental role in cardiovascular homeostasis by modulation of fluid and electrolyte balance and vascular tone. C-type natriuretic peptide (CNP) represents the paracrine element of the natriuretic peptide axis which complements the endocrine actions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). CNP is produced by the endothelium and the heart and appears to play a prominent role in vascular and cardiac function, both physiologically and pathologically. This provides a rationale for the therapeutic potential of pharmacological interventions targeted to CNP signalling. This article provides an overview of the biology and pharmacology of CNP, with emphasis on the cardiovascular system, and discusses pathologies in which drugs designed to manipulate CNP signalling maybe of clinical benefit.

Topics: Animals; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Natriuretic Peptide, C-Type; Receptors, Atrial Natriuretic Factor

The natriuretic peptide system includes three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They contribute to the regulation of cardiovascular homeostasis through diuretic, natriuretic, and vasodilatory properties. Among them, ANP has received particular attention because of its effects on blood pressure regulation and cardiac function. Although the potential for its therapeutic application in the treatment of hypertension and heart failure has been evaluated in several experimental and clinical investigations, no pharmacological approach directly targeted at modulation of ANP levels has ever reached the stage of being incorporated into clinical practice. Recently, ANP has also received attention as being a possible cardiovascular risk factor, particularly in the context of hypertension, stroke, obesity, and metabolic syndrome. Abnormalities in either peptide levels or peptide structure are thought to underlie its implied role in mediating cardiovascular diseases. Meanwhile, BNP has emerged as a relevant marker of left ventricular (LV) dysfunction and as a useful predictor of future outcome in patients with heart failure. This review deals with the major relevant findings related to the cardiovascular and metabolic effects of natriuretic peptides, to their potential therapeutic use, and to their role in mediating cardiovascular diseases.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Fibrosis; Humans; Inflammation; Insulin Resistance; Lipid Metabolism; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Risk Factors; Ventricular Dysfunction, Left; Ventricular Remodeling

In recent years, biomarkers have been recognized as important tools for diagnosis, risk stratification, and therapeutic decision-making in cardiovascular diseases. Currently, the clinical potential of several natriuretic peptides is under scientific investigation. The well-known counter-regulatory hormones are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP) and urodilatin, which play an important role in the homeostasis of body fluid volume. ANP and BNP have already been demonstrated to have diagnostic usefulness in a great number of studies, which have progressed from bench to bedside. This article summarizes existing data on ANP and related peptides in cardiovascular and other disorders, and outlines the potential clinical usefulness of these markers.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Elapid Venoms; Homeostasis; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Peptide Fragments; Peptides

Natriuretic peptides (NPs) are released from the heart in response to pressure and volume overload. B-type natriuretic peptide (BNP) and N-terminal-proBNP have become important diagnostic tools for assessing patients who present acutely with dyspnea. The NP level reflects a compilation of systolic and diastolic function as well as right ventricular and valvular function. Studies suggest that using NPs in the emergency department can reduce the consumption of hospital resources and can lower costs by either eliminating the need for other, more expensive tests or by establishing an alternative diagnosis that does not require hospital stay. Caveats such as body mass index and renal function must be taken into account when analyzing NP levels. Natriuretic peptide levels have important prognostic value in multiple clinical settings, including in patients with stable coronary artery disease and with acute coronary syndromes. In patients with decompensated heart failure due to volume overload, a treatment-induced drop in wedge pressure is often accompanied by a rapid drop in NP levels. Knowing a patient's NP levels might thus assist with hemodynamic assessment and subsequent treatment titration. Monitoring NP levels in the outpatient setting might also improve patient care and outcomes.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Death, Sudden, Cardiac; Heart Diseases; Heart Failure; Hemodynamics; Humans; Kidney Failure, Chronic; Monitoring, Physiologic; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Obesity; Peptide Fragments; Prognosis; Pulmonary Edema; Pulmonary Embolism; Pulmonary Wedge Pressure; Renal Dialysis; Stroke; Weight Loss

Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed throughout the vasculature and is found in particularly high concentrations in the endothelium. Recent studies demonstrate that CNP is a novel endothelium-derived hyperpolarising factor (EDHF) that complements the actions of other endothelial vasorelaxant mediators such as nitric oxide (NO) and prostacyclin. Since several cardiovascular disorders are associated with dysfunction of natriuretic peptide activity, selective modulation of the natriuretic peptide pathways represents an important therapeutic target; whilst this has been exploited to some degree in terms of ANP/BNP, the therapeutic potential of CNP has yet to be tapped. This review focuses on recent findings on the actions and mechanism of locally produced endothelial-derived CNP in the cardiovascular system and highlights many potential avenues for therapeutic intervention, via modulation of CNP-signalling, in cardiovascular disease.

Topics: Amino Acid Sequence; Animals; Biological Factors; Blood Vessels; Cardiovascular Diseases; Endothelium, Vascular; Humans; Molecular Sequence Data; Natriuretic Peptide, C-Type; Natriuretic Peptides; Receptors, Neuropeptide; Signal Transduction

Thus far, five molecules comprise the natriuretic peptide family (NPF): ANP, urodilatin, BNP, CNP and DNP. Precursor hormones for ANP, BNP and CNP are encoded by a different gene. Final peptides are ligands for A, B and C receptors, acting the latter as a clearance receptor besides neutral endopeptidase (EC 24.11). cGMP acts as a second messenger. Natriuretic peptides (NP) have well-known functions such as natriuretic, antihypertensive and reduction of plasma renin-aldosterone concentrations. An antiinflammatory ANP potential and a pro-apoptotic action in rats endothelial cells of different NP have been described. Unlike adults, NP show a different distribution during ontogeny and a different pattern of excretion under different stimuli. Noncompetitive immunoassays have become more suitable than competitive ones for routine measurement of NP with recent advances in speed of measurement. BNP and pro-BNP are emerging as useful tools in diagnosis, management and prognosis of heart disease. Preliminary data support a role of NP in the therapy of congestive heart failure. Finally, potential therapeutic compounds of NP in different pathologies are updated with an important focus on vasopeptidase inhibitors. These are capable of strengthening NP and inhibiting renin-angiotensin system at the same time, as potential useful molecules in cardiovascular therapy.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments

Endothelium-derived hyperpolarising factor (EDHF) is an important regulator of vascular tone; however, its identity is still unclear. Several different molecules have been suggested, the most recent of which is the 22-amino acid peptide C-type natriuretic peptide (CNP). CNP induces hyperpolarisation and relaxation of rat mesenteric resistance artery vascular smooth muscle through activation of natriuretic peptide receptor subtype C (NPR-C) and the same potassium channels as EDHF. In addition, this peptide is released from endothelial cells of the perfused rat mesenteric bed in response to endothelium-dependent vasodilators. Thus, CNP is likely to play a vital role in regulation of vascular tone. In addition, since there is evidence that up-regulation of EDHF occurs where normal endothelium function has been compromised, modulation of this pathway represents a novel target for therapeutics in the treatment of inflammatory cardiovascular pathologies characterised by endothelial dysfunction.

Topics: Animals; Biological Factors; Cardiovascular Diseases; Endothelium, Vascular; Humans; Natriuretic Peptide, C-Type

The natriuretic peptides are a group of structurally related but genetically distinct peptides. Four types of natriuretic peptides have been found thus far: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and Dendroaspis natriuretic peptide (DNP). ANP and BNP are secreted mainly from the heart and function as hormones with vasodilatory and natriuretic effects. CNP originates mainly from endothelial cells with a paracrine effect to induce vasodilation. Other effects of natriuretic peptides including negative inotropy, antimitogenic and anticoagulation have been described. Three types of natriuretic peptide receptors mediate their functions, and among them two are cGMP-coupled. Clearance of natriuretic peptides is via its clearance receptor through the action of neutral endopeptidases. Natriuretic peptides interact with other vasoactive peptides including endothelin. The putative role of natriuretic peptides in the pathophysiology of various cardiovascular diseases including congestive heart failure, hypertension, ischemic heart disease, and cardiomyopathy are discussed. Natriuretic peptide plasma levels are used for the diagnosis and therapeutic follow-up of congestive heart failure patients. Increasing the levels of natriuretic peptides by natriuretic peptide mimetics and neutral endopeptidase inhibitors may provide a new therapeutic strategy for the treatment of cardiovascular diseases such as congestive heart failure and hypertension.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Cardiovascular Diseases; Elapid Venoms; Endothelin-1; Humans; Intercellular Signaling Peptides and Proteins; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptides; Protease Inhibitors

In recent years, biomedical science has witnessed the emergence of peptide biochemicals as significant topics of research. Some of these peptides are of little potential clinical use, while others, of which cardiac natriuretic peptides are an example, appear to be promising. This particular group of peptides (i.e. ANP, BNP and CNP) shows promising diagnostic as well as therapeutic potential for various pathological conditions. In the case of acute myocardial infarction, these peptides have significant diagnostic and predictive properties, more so than other biochemicals such as adrenaline, renin and aldosterone. In addition, ANP is found to have significant benefits over the classical anti-anginal drug glyceryl trinitrate. However, as is the case with other peptides, applying these benefits clinically may not be easy because of the structure of the compounds, but various strategies are now being applied to solve this problem. These include the use of non-peptide receptor ligands, inhibitors of ANP metabolism, gene therapy and so on. The development of drugs in clinical practice, which exploits the natriuretic peptides system therefore seems to be promising, and this article reviews advances in our understanding of these compounds.

Topics: Alzheimer Disease; Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Liver Cirrhosis; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Receptors, Atrial Natriuretic Factor

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Cattle; Dogs; Heart Failure; Humans; Hypertension; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; RNA, Messenger; Swine; Vasodilation

Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP1-98) are differently regulated in their production/secretion patterns and clearance rates; consequently, the assay for these peptides may provide complementary (or even different) pathophysiological and/or clinical information. The assay for cardiac natriuretic peptides has been utilized in clinical conditions associated with expanded fluid volume. In particular, this assay can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered a prognostic indicator of long-term survival in patients with heart failure and/or after acute myocardial infarction. Non-competitive immunometric assays (such as two-site IRMAs), even if more expensive, seem to be preferable to RIAs for routinary assay of cardiac peptide hormones because they generally have a better degree of sensitivity, accuracy, and precision.

Topics: Amino Acid Sequence; Atrial Natriuretic Factor; Cardiovascular Diseases; Diabetes Mellitus; Humans; Kidney Diseases; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Protein Precursors

Topics: Amino Acid Sequence; Atrial Natriuretic Factor; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Central Nervous System; Humans; Kidney; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Receptors, Atrial Natriuretic Factor

C-type natriuretic peptide (CNP) is a 22-amino-acid peptide, structurally related to but genetically distinct from atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whereas ANP and BNP are ligands for a guanylyl cyclase-coupled receptor, the NPR-A receptor, CNP is a specific ligand for the NPR-B receptor. In addition to clearance by the NPR-C receptor, CNP is subject to degradation by the ectoenzyme neutral endopeptidase 24.11 (NEP), which is widely distributed in the kidney, lung, heart, and endothelial cells. Although initially identified in porcine brain, CNP immunoreactivity has been found in human vascular endothelial cells, plasma, and kidney. CNP has potent systemic cardiovascular actions, which include reductions in cardiac filling pressures and output, secondary to vasorelaxation and decreases in venous return, but has minimal renal actions. Unlike ANP, CNP is a selective endothelium-independent venodilator. However, it is also a potent coronary vasodilator. Expression of the CNP gene by the endothelial cells, the presence of CNP receptors on vascular smooth muscle cells (VSMCs), and the antimitogenic effect of CNP on VSMCs suggest that CNP is produced by the endothelium and acts on adjacent VSMCs serving as an autocrine/paracrine endothelium-derived vasoregulatory system.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Endothelium, Vascular; Humans; Models, Cardiovascular; Molecular Sequence Data; Natriuretic Peptide, C-Type

In this study, we aimed to demonstrate the effectiveness of serum amino-terminal proCNP (NT-proCNP) levels in predicting coronary heart disease (CHD) and cardiovascular risk in type 2 diabetes mellitus (T2DM) patients.. We recruited 73 patients with T2DM in the study. Additionally, we grouped the patients according to their status of diabetic retinopathy (DR) as no DR, non-proliferative DR, or proliferative DR. Serum NT-proCNP levels of the patients were measured and their atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated.. There was no significant difference in terms of NT-proCNP levels between the groups (p = 0.3) and in terms of CHD and ASCVD risk scores (p = 0.4 and p = 0.4, respectively). In the correlation analysis, a significant correlation was observed between the NT-proCNP levels and the ASCVD risk score (r = 0.373; p = 0.008 among the entire cohort and r = 0.555; p = 0.01 in the non-proliferative-DR group), smoking status (r = 0.280; p = 0.03 among the entire cohort and r = 0.362; p = 0.035 in the non-proliferative-DR group), sBP (r = 0.278; p = 0.038 among the entire cohort), and dBP (r = 0.284; p = 0.034 among the entire cohort and r = 0.482; p = 0.004 in the proliferative-DR group). In the ROC analysis, we found that the NT-proCNP level predicted a high ASCVD risk score with 83.3% sensitivity and 70.8% specificity and a very high ASCVD risk score with 100% sensitivity and 69.2% specificity among the proliferative-DR patients. No cut-off value was calculated for the prediction of high and very-high ASCVD risk scores in patients with non-proliferative DR. Similarly, no cut-off value was revealed for the prediction of established coronary artery disease in all groups.. Our study revealed a significant association between NT-proCNP levels and high ASCVD risk scores in patients with proliferative DR.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Heart Disease Risk Factors; Humans; Natriuretic Peptide, C-Type; Risk Factors

Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders.

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Homeostasis; Metabolic Diseases; Mice; Mice, Knockout; Natriuretic Peptide, C-Type; Receptors, Atrial Natriuretic Factor; Thermogenesis

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Macrophages; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Receptors, LDL

Ageing-related alterations in cardiovascular structure and function are commonly associated with chronic inflammation. A potential blood-based biomarker indicative of a chronic inflammatory state is N-Terminal Pro C-Type Natriuretic Peptide (NTproCNP). We aim to investigate associations between NTproCNP and ageing-related impairments in cardiovascular function. Community-based participants underwent same-day assessment of cardiovascular function and circulating profiles of plasma NTproCNP. Associations between cardiovascular and biomarker profiles were studied in adjusted models including standard covariates. We studied 93 participants (mean age 73 ± 5.3 years, 36 women), of whom 55 (59%) had impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s) <0.84). Participants with impaired myocardial relaxation were also found to have lower peak early phase filling velocity (0.6 ± 0.1 vs 0.7 ± 0.1, p < 0.0001) and higher peak atrial phase filling velocity (0.9 ± 0.1 vs 0.7 ± 0.1, p < 0.0001). NTproCNP levelswere significantly lower among participants with impaired myocardial relaxation (16.4% vs 39.5% with NTproCNP ≥ 19, p = 0.012). After multivariable adjustments, NTproCNP was independently associated with impaired myocardial relaxation (OR 2.99, 95%CI 1.12-8.01, p = 0.029). Community elderly adults with myocardial ageing have lower NTproCNP levels compared to those with preserved myocardial function. Given that impaired myocardial relaxation probably represents early changes within the myocardium with ageing, NTproCNP may be useful as an 'upstream' biomarker useful for charting myocardial ageing.

Topics: Aged; Aging; Biomarkers; Blood Flow Velocity; Cardiovascular Diseases; Diastole; Female; Geriatrics; Humans; Inflammation; Male; Myocardium; Natriuretic Peptide, C-Type

C-type natriuretic peptide (CNP) is an endothelium-derived peptide that is released as a protective mechanism in response cardiovascular injury or disease. However, no studies have investigated circulating CNP, identifying clinical factors that may influence CNP and its relationship to cardiovascular disease in the general population. We studied 1841 randomly selected subjects from Olmsted County, MN (mean age, 63±11 years; 48% men). Plasma CNP was measured by a well-established radioimmunoassay and echocardiography, clinical characterization, and detailed medical record review were performed. We report that CNP circulates at various concentrations (median, 13 pg/mL), was unaffected by sex, was weakly associated by age, and that highest quartile of CNP identified a high-risk phenotype. Subjects with CNP in the highest quartile were associated with increased risk of myocardial infarction (multivariable-adjusted hazard ratio, 1.51; 95% confidence interval, 1.09-2.09; P=0.01) but not heart failure, cerebrovascular accidents, or death during a follow-up of 12 years. Addition of the highest quartile of CNP to clinical variables led to a modest increase in the integrated discrimination improvement for risk of myocardial infarction. In a large community-based cohort, elevated circulating CNP identified a high-risk phenotype that included cardiovascular comorbidities and left ventricular dysfunction, and provided evidence that highest concentrations of CNP potentially has prognostic value in predicting future risk of myocardial infarction. Together, these data from the general population highlight the potential value of CNP and support the need for additional studies to evaluate whether mechanisms regulating CNP could improve outcomes.

Topics: Age Factors; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Confidence Intervals; Databases, Factual; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, C-Type; Odds Ratio; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Rate

Topics: Cardiovascular Diseases; Humans; Natriuretic Peptide, C-Type

The high prevalence of obesity in children may increase the magnitude of lifetime risk of cardiovascular disease (CD). At present, explicit data for recommending biomarkers as routine pre-clinical markers of CD in children are lacking. C-type natriuretic peptide (CNP) is assuming increasing importance in CD; in adults with heart failure, its plasma levels are related to clinical and functional disease severity. We have previously reported five different reference intervals for blood CNP as a function of age in healthy children; however, data on plasma CNP levels in obese children are still lacking. Aim of this study was to assess CNP levels in obese adolescents and verify whether they differ from healthy subjects. Plasma CNP was measured in 29 obese adolescents (age: 11.8 ± 0.4 years; BMI: 29.8 ± 0.82) by radioimmunoassay and compared with the reference values of healthy subjects. BNP was also measured. Both plasma CNP and BNP levels were significantly lower in the obese adolescents compared to the appropriate reference values (CNP: 3.4 ± 0.2 vs 13.6 ± 2.3 pg/ml, p<0.0001; BNP: 18.8 ± 2.6 vs 36.9 ± 5.5 pg/ml, p=0.003). There was no significant difference between CNP values in males and females. As reported in adults, we observed lower plasma CNP and BNP levels in obese children, suggesting a defective natriuretic peptide system in these patients. An altered regulation of production, clearance and function of natriuretic peptides, already operating in obese adolescents, may possibly contribute to the future development of CD. Thus, the availability of drugs promoting the action of natriuretic peptides may represent an attractive therapeutic option to prevent CD.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Female; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Obesity; Radioimmunoassay; Reference Values

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type

C-type natriuretic peptide (CNP) is a paracrine molecule with effects on endothelial integrity, vascular tone and atherosclerotic process. Arterial stiffness, wave reflections, endothelial dysfunction and carotid intima-media thickness (IMT) are predictors of cardiovascular events. We investigated whether CNP is related to arterial structure and function in men.. We evaluated arterial structural and functional characteristics in 117 consecutive men (mean age 57.3 + or - 9.2 years), with and without cardiovascular risk factors, who had no established cardiovascular disease. Arterial elastic properties were evaluated with carotid-femoral pulse wave velocity (PWV), wave reflections with augmentation index (AIx), endothelial function with flow-mediated dilatation of the brachial artery (FMD) and early atherosclerosis with carotid IMT. Amino-terminal proCNP (NT-proCNP) was assessed in venous blood.. The number of cardiovascular risk factors was inversely related to levels of NT-proCNP (P<0.01) and there was a progressive increase in Framingham risk score according to decreasing tertiles of NT-proCNP (P<0.001). In multivariable regression analysis NT-proCNP exhibited significant negative associations with PWV and IMT and positive association with FMD (all P<0.05) that were independent of age, blood pressure, smoking habits, body mass index, blood glucose, total triglycerides, low-density lipoprotein and endothelin-1 or high-sensitivity C-reactive protein. There was no relation between NT-proCNP and AIx.. The present study is the first to demonstrate in a global arterial approach relationship between CNP and functional and early structural arterial changes. These findings elucidate pathophysiological links and may have important clinical implications for the estimation of cardiovascular risk in men.

Topics: Aged; Arteries; Atherosclerosis; Cardiovascular Diseases; Carotid Arteries; Elasticity; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Natriuretic Peptide, C-Type; Risk Factors; Tunica Intima; Tunica Media

The natriuretic peptide system comprises three structurally related peptides: atrial natriuretic peptide, B-type natriuretic peptide and C-type natriuretic peptide. In circulation, they play an important endocrine role in the regulation of cardiovascular homeostasis by maintaining blood pressure and extracellular fluid volume. Atrial natriuretic peptide and B-type natriuretic peptide have gained considerable diagnostic interest as biomarkers in cardiovascular disease. By contrast, C-type natriuretic peptide has not yet been ascribed a role in human diagnostics. This perspective aims at recapitulating the present biochemical and clinical issues concerning C-type natriuretic peptide measurement in plasma as a potential biomarker.

Topics: Amino Acid Sequence; Biomarkers; Cardiovascular Diseases; Humans; Molecular Sequence Data; Natriuretic Peptide, C-Type; Prognosis; Sequence Homology, Amino Acid

Production and clearance of plasma C-type natriuretic peptide (CNP) and amino terminal (NT)-proCNP immunoreactivity in the human circulation remain poorly characterized. Accordingly, we have measured arterial and venous concentrations of CNP and NT-proCNP across multiple tissue beds during cardiac catheterization in 120 subjects (age: 64.2+/-9.0 years; 73% men) investigated for cardiovascular disorders. The heart, head and neck, and musculoskeletal tissues made the clearest contributions to both plasma CNP and NT-proCNP (P<0.05). Net release of NT-proCNP was also observed from hepatic tissue (P<0.001). Negative arteriovenous gradients for CNP were observed across renal, hepatic, and pulmonary tissue (P<0.05), indicating net clearance, whereas no tissue-specific site of NT-proCNP clearance was identified. Age, mean pulmonary artery pressure, left ventricular end diastolic pressure, Brandt score of myocardial jeopardy, and troponin I were independent predictors of circulating CNP levels in multivariable analysis. Sex and kidney function were independently predictive of arterial NT-proCNP. The proportional step-up of CNP (+60%) across the heart was less than for brain natriuretic peptide (+123%) but greater than for NT-pro-brain natriuretic peptide (NT-proBNP) (+36%) and NT-proCNP (+42%; P<0.001 for all). We conclude that cardiac and head and neck tissue are important sources of CNP. Circulating CNP but not NT-proCNP concentrations are related to cardiac hemodynamic load and ischemic burden. Although cardiac release is most evident, multiple additional tissues release NT-proCNP immunoreactivity without evidence for an organ-specific site for NT-proCNP degradation. Taken together, differences in magnitude and direction of transorgan gradients for CNP compared with NT-proCNP suggest net generalized cosecretion with differing mechanisms of clearance.

Topics: Aged; Cardiovascular Diseases; Echocardiography; Female; Hemodynamics; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Peptide Fragments; Protein Precursors; Radioimmunoassay

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Heart; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type

Recently we have found that C-type natriuretic peptide (CNP) inhibits proliferation of cultured rat vascular smooth muscle cells through an elevation of cGMP. We have now tested whether administration of CNP inhibits the development of intimal lesions induced by air-drying injury in rat common carotid arteries in vivo. CNP treatment (1 microgram/kg per min, iv infusion) for either 14 or 5 days resulted in 70% or 60% reduction, respectively, of intimal cross-section area 14 days after injury as compared with control rats. We also found that CNP potently stimulated cGMP production in injured carotid arteries with intimal thickening, but not in intact ones. These results indicate that GC-B, CNP specific receptor/guanylyl cyclase, is expressed at the sites of vascular injury, and that CNP might be efficacious in the prevention of restenosis caused by intimal thickening following coronary angioplasty.

Topics: Animals; Cardiovascular Diseases; Carotid Arteries; Cyclic GMP; Endothelium, Vascular; Guanylate Cyclase; Male; Natriuretic Peptide, C-Type; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins