stilbenes and Heart-Failure

Despite existing therapies, patients with heart failure have a very poor quality of life and a high 1-year mortality rate. Given the impact of this syndrome on health outcomes, research is being directed toward identifying novel strategies to treat heart failure symptoms as well as to prolong survival. One molecule that has been tested in animal models for this purpose is resveratrol. Resveratrol is a naturally occurring polyphenol found in several plants, and administration of resveratrol has been shown to prevent and/or slow the progression of heart failure in animal models of heart failure induced by myocardial infarction, pressure overload, myocarditis, and chemotherapy-induced cardiotoxicity. In addition, some animal studies have shown that resveratrol improves cardiac function and survival when administered as a treatment for established heart failure. Furthermore, as heart failure induces alterations in skeletal muscle and vasculature that also contribute to certain heart failure symptoms, such as fatigue and exercise intolerance, it has also been shown that resveratrol acts on these peripheral tissues to improve skeletal muscle and endothelial/vascular function. Therefore, if these animal studies translate to humans, resveratrol may prove to be a novel therapy for the treatment of heart failure.

Topics: Animals; Cardiotonic Agents; Heart Failure; Humans; Resveratrol; Stilbenes

The concept of food has expanded beyond its traditional role of survival and hunger satisfaction, to include a role in the prevention and treatment of disease. Polyphenols are classes of compounds that are synthesized by plants to serve a wide variety of functions including growth pollination and defense. These compounds have recently received increased attention in medical research. In this group, one of the most studied has been resveratrol (3,5,4,-trihydroxystilbene), a polyphenol, which is found predominantly in grapes and berries. Over the past two decades, researchers have studied the ability of resveratrol to prevent or reverse the development of abnormalities in heart structure and function in animal models of heart disease and heart failure. The results from animal studies have been promising, and very recently, this knowledge has been translated into examining the efficacy of resveratrol in humans with heart disease/failure. In this review we will discuss the current status of resveratrol research on cardioprotection.

Topics: Animals; Cardiotonic Agents; Heart Failure; Humans; Resveratrol; Stilbenes; Vitis

Resveratrol is a well-known antioxidant that exists in grape skin/seed, red wine, and the root of Polygonum cuspidatum, a traditional Chinese and Japanese medicinal material. Studies have found that resveratrol has many interesting properties, including anti-carcinogenic properties, anti-microbial and antiviral effects, the ability to reverse dyslipidemia and obesity, the ability to attenuate hyperglycemia and hyperinsulinemia, and the ability to protect endothelial function. Heart failure is the final consequence of the majority of cardiovascular diseases, and resveratrol has been shown to directly attenuate heart contraction. The cardiovascular protective capacities of resveratrol are associated with multiple molecular targets and may lead to the development of novel therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, and heart failure. This article will mainly review recently published basic researches about the protective cardiovascular effects of resveratrol because these results may lead to the development of new clinical therapeutics in patients.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Antioxidants; Cardiovascular Diseases; Heart Failure; Humans; Resveratrol; Sirtuin 1; Stilbenes

Calorie restriction is considered to be the best environmental intervention providing health benefits to mammals. The underlying mechanism of this intervention seems to be controlled by a group of NAD-dependent deacetylases, collectively called sirtuins. In mammals, there are seven sirtuin analogs, SIRT1-SIRT7. The founding member of this family, SIRT1, is shown to protect cardiomyocytes from apoptosis and age-dependent degeneration in a dose dependent manner-protecting cells at low doses but showing detrimental effects at high doses. Studies performed with overexpression or knockdown of SIRT1 indicated that, although it protects cells from oxidative stress and ischemia-reperfusion injury, it promotes hypertrophy of cardiomyocytes. Activation of endogenous SIRT1 by resveratrol also displayed pro-survival and pro-hypertrophic activity of SIRT1. In this article, we review recent findings documenting the role of SIRT1 in regulating cardiac myocyte growth and survival under stress, and the proposed mechanism behind its cardioprotective effects. We also briefly discuss two other sirtuin analogs which have been shown to have cardioprotective effects. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".

Topics: Animals; Cardiomegaly; Cell Survival; Coronary Vessels; Enzyme Activators; Gene Expression; Heart Failure; Humans; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

The prevalence of heart diseases, such as coronary artery disease and congestive heart failure, increases with age. Optimal therapeutic interventions that antagonize aging may reduce the occurrence and mortality of adult heart diseases. We discuss here how molecular mechanisms mediating life span extension affect aging of the heart and its resistance to pathological insults. In particular, we review our recent findings obtained from transgenic mice with cardiac-specific overexpression of Sirt1, which demonstrated delayed aging and protection against oxidative stress in the heart. We propose that activation of known longevity mechanisms in the heart may represent a novel cardioprotection strategy against aging and certain types of cardiac stress, such as oxidative stress.

Topics: Aging; Animals; Apoptosis; Caloric Restriction; Heart; Heart Diseases; Heart Failure; Humans; Longevity; Mice; Nicotinamide Phosphoribosyltransferase; Oxidative Stress; Resveratrol; Saccharomyces cerevisiae; Sirtuin 1; Sirtuins; Stilbenes; Up-Regulation

Heart failure is one of the diseases with the highest mortality in the world, and inflammation is the main cause for its occurrence and development. The stilbene skeleton of resveratrol has been shown to have excellent anti-inflammatory and antioxidant activities. In order to continue our research on dihydropyrazole derivatives, a series of novel (E)-4-methyl-2-(3-phenyl-5-(4-styrylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives were designed and synthesized according to the principle of molecular hybridization for evaluation their anti-inflammatory and antioxidation activities. We screened their anti-inflammatory abilities in RAW264.7 cells and analyzed the preliminary structure-activity relationship, and explored the related molecular mechanisms. We further used doxorubicin (DOX)-induced heart failure model to explore the protective role of our compound in vivo. Our results showed that compound F5 exhibited the most potent activity and was superior to the positive control. It reversed the expression of lipopolysaccharide (LPS)-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and superoxide dismutase 1 (SOD1) in RAW264.7 cells. In addition, compound F5 also inhibited DOX-induced inflammation and reactive oxygen species by modulating the p38/nuclear factor kappa B (NF-κB) signaling pathway in H9C2 cells. In vivo results showed that compound F5 ameliorated DOX-caused damage, such as reduced left ventricular ejection fraction, severe inflammation, fibrosis and oxidative stress in heart. In conclusion, compound F5 could be used as a promising agent for the treatment of heart failure through attenuating oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Doxorubicin; Heart Failure; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Signal Transduction; Stilbenes; Stroke Volume; Tumor Necrosis Factor-alpha; Ventricular Function, Left

This study explored the effect of pterostilbene (PTS) complexed with hydroxypropyl-β-cyclodextrin (HPβCD) on right heart function, glutathione and glutaredoxin systems, and the expression of redox-sensitive proteins involved with regulation calcium levels in the experimental model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). After 7 days of PAH induction, rats received daily doses of the PTS:HPβCD complex (corresponding to 25, 50, or 100 mg·kg

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antioxidants; Calcium; Echocardiography; Glutathione; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Lipid Peroxidation; Male; Monocrotaline; Oxidative Stress; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stilbenes; Stroke Volume

Piceatannol, a grape-derived polyphenol, has been linked to proarrhythmic properties by aggravating inhomogeneous conduction delay in the ischemia-reperfusion (IR) zone to enhance arrhythmogenic alternans in heart failure (HF) rabbits. The underlying molecular mechanisms of piceatannol-induced conduction disturbance were unclear in this model.. HF was induced by 4 weeks' rapid ventricular pacing. IR injury was induced in vivo using a protocol of left coronary artery ligation and release. Left ventricular cardiomyocytes were isolated enzymatically for whole-cell patch-clamp studies. Piceatannol (10 μM) was administrated to test its inhibitory effect on sodium current (I. Peak I. Downregulation of NaV 1.5 protein expression and reduced peak I

Topics: Animals; Blotting, Western; Down-Regulation; Heart Failure; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Rabbits; Reperfusion Injury; Stilbenes

A short-term exposure to resveratrol at high dosages exerts a remarkable cardioprotective effect. Whether a long-term exposure to resveratrol at low dosages that can be obtained through consumption of a resveratrol-rich diet is beneficial to heart diseases is unknown. We tested the effects of a resveratrol-enriched diet on cardiovascular remodeling of chronic heart failure (CHF) in rats resulting from permanent ligation of left coronary artery. Two weeks after surgery, rats were started on either a resveratrol-enriched (R; 5 mg/kg per day; n = 23) or normal (Control; n = 23) diet for next 10 months. Serial echocardiography in Control showed a significant decline in LV ejection fraction, increases in LV end-systolic and end-diastolic volumes, and expansion in myocardial infarct from pre-treatment values. In R, compared with Control, there were substantial improvements in those parameters. End-point LV pressure-volume loop analysis showed a significantly improved LV systolic function and AV-coupling, an index of energy transfer efficacy between the heart and aortic tree, in R compared with Control (p < 0.05). Aortic pulse wave velocity, a measure of arterial stiffness, was significantly lower in R (389 ± 15 cm/s; p < 0.05) compared with Control (489 ± 38 cm/s). These results demonstrated that long-term dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in CHF.

Topics: Animals; Cardiotonic Agents; Chronic Disease; Collagen; Dietary Supplements; Disease Models, Animal; Drug Administration Schedule; Echocardiography; Fibrosis; Heart Failure; Male; Myocardial Contraction; Myocardium; Pulse Wave Analysis; Rats, Wistar; Resveratrol; Stilbenes; Stroke Volume; Time Factors; Vascular Stiffness; Ventricular Function, Left; Ventricular Remodeling

Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,40-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,20,60-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-40-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown,abolished these anti-hypertrophiceffects. In contrast,resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxationtime(an indicator of diastolicdys function),and this was improved by stilbenoid treatment.In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy,a major risk factor for heart failure,may be context-dependent and requires furtherstudy.

Topics: Animals; Blood Pressure; Cardiomegaly; Cell Survival; Disease Models, Animal; Heart Failure; Heart Function Tests; MAP Kinase Signaling System; Myocytes, Cardiac; Polyphenols; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg

Topics: Animals; Antioxidants; Energy Metabolism; Exercise Tolerance; Fatigue; Glucose; Heart Failure; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Microbiota; Muscle, Skeletal; Oxidation-Reduction; Oxygen Consumption; Physical Conditioning, Animal; Physical Exertion; Resveratrol; Stilbenes; Stroke Volume

Recent evidence suggests that polydatin (PD), a resveratrol glucoside, may have beneficial actions on the cardiac hypertrophy. Therefore, the current study focused on the underlying mechanism of the PD anti-hypertrophic effect in cultured cardiomyocytes and in progression from cardiac hypertrophy to heart failure in vivo. Experiments were performed on cultured neonatal rat, ventricular myocytes as well as adult mice subjected to transverse aortic constriction (TAC). Treatment of cardiomyocytes with phenylephrine for three days produced a marked hypertrophic effect as evidenced by significantly increased cell surface area and atrial natriuretic peptide (ANP) protein expression. These effects were attenuated by PD in a concentration-dependent manner with a complete inhibition of hypertrophy at the concentration of 50 µM. Phenylephrine increased ROCK activity, as well as intracellular reactive oxygen species production and lipid peroxidation. The oxidizing agent DTDP similarly increased Rho kinase (ROCK) activity and induced hypertrophic remodeling. PD treatment inhibited phenylephrine-induced oxidative stress and consequently suppressed ROCK activation in cardiomyocytes. Hypertrophic remodeling and heart failure were demonstrated in mice subjected to 13 weeks of TAC. Upregulation of ROCK signaling pathway was also evident in TAC mice. PD treatment significantly attenuated the increased ROCK activity, associated with a markedly reduced hypertrophic response and improved cardiac function. Our results demonstrated a robust anti-hypertrophic remodeling effect of polydatin, which is mediated by inhibition of reactive oxygen species dependent ROCK activation.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Animals, Newborn; Atrial Natriuretic Factor; Cardiomegaly; Cardiotonic Agents; Cell Size; Cells, Cultured; Disease Models, Animal; Drugs, Chinese Herbal; Glucosides; Heart Failure; Heart Ventricles; Male; Mice, Inbred C57BL; Oxidative Stress; Phenylephrine; Rats; rho-Associated Kinases; Stilbenes; Ventricular Remodeling

SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro.. We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.. SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes.. These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

Topics: Animals; Apoptosis; Cell Line; Doxorubicin; Gene Expression Regulation; Heart Failure; Humans; Mice; Myocytes, Cardiac; Niacinamide; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

Pressure overload has an important role in heart failure, inducing excessive autophagy in cardiac myocytes that is considered to be pathogenic. Resveratrol has been reported to improve cardiac dysfunction induced by pressure overload, but it has been unclear whether resveratrol ameliorates cardiac dysfunction by regulating autophagy. In this study, heart failure was induced in rats by constriction of the abdominal aorta. Four weeks after surgery, the rats with heart failure were randomized to treatment with resveratrol (8 mg · kg(-1) · d(-1) by intraperitoneal injection) for 28 days or to intraperitoneal injection of the vehicle (propylene glycol) alone. Echocardiography was performed to assess cardiac function. Expression of brain natriuretic peptide messenger RNA in the left ventricle was detected by real-time polymerase chain reaction, whereas expression of proteins associated with autophagy (beclin-1 and lamp-1) was detected by western blotting and immunohistochemistry. Furthermore, autophagic vacuoles were detected in the heart by transmission electron microscopy, and the myocardial ATP content was measured by the bioluminescence method. Treatment with resveratrol significantly improved cardiac dysfunction and reduced brain natriuretic peptide expression in rats with heart failure. Resveratrol down-regulated beclin-1 and lamp-1 expression and also inhibited the formation of autophagic vacuoles in failing hearts. Furthermore, resveratrol restored the myocardial ATP level and reduced phosphorylation of AMP-activated protein kinase at Thr172. These results suggest that resveratrol may inhibit autophagy through inactivation of AMP-activated protein kinase and restoration of ATP in heart failure induced by pressure overload. Accordingly, resveratrol may be beneficial for patients with hypertensive heart disease.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Autophagy; Blotting, Western; Cardiotonic Agents; Disease Models, Animal; Heart Failure; Heart Function Tests; Hypertension; Male; Myocardium; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Piceatannol, a hydroxystilbene natural product, has been reported to exert antiarrhythmic action via INa inhibition and slow INa inactivation in ischemia-reperfused (IR) rat hearts. The present study aimed to clarify the proarrhythmic property of piceatannol during regional IR injury in failing rabbit hearts.. Heart failure (HF) was induced by rapid right ventricular pacing for 4 weeks. The IR model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo. Simultaneous voltage and intracellular Ca(2+) (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts (n=11 in each HF and control group). Action potential duration (APD) restitution, arrhythmogenic alternans and VF inducibility were evaluated by a dynamic pacing protocol. Conduction velocity was measured along lines across the IR and non-IR zones during pacing. Piceatannol (10 μM) was administered after baseline studies.. In the HF group, piceatannol decreased conduction velocity, induced rate-dependent regional inhomogeneity of conduction delay and wavelength shortening, slowed Cai decay, and facilitated arrhythmogenic alternans instead of APD prolongation to increase VF inducibility. In the control group, the proarrhythmic effects of piceatannol on APD restitution, arrhythmogenic alternans and conduction delay were offset by its antiarrhythmic effects (APD and wavelength prolongation), resulting in a neutral effect on VF inducibility.. Piceatannol (10 μM) is proarrhythmic in failing rabbit hearts with regional IR injury. The increased VF inducibility by piceatannol in HF suggests that its undesirable effects are more pronounced than its benefits in failing hearts.

Topics: Animals; Calcium; Disease Models, Animal; Electrophysiologic Techniques, Cardiac; Heart Block; Heart Conduction System; Heart Failure; Myocardial Reperfusion Injury; Perfusion; Protein-Tyrosine Kinases; Rabbits; Stilbenes; Ventricular Fibrillation

Reduced AMP-activated protein kinase (AMPK) expression has been shown to play a significant role in the cardiac dysfunction in heart failure. This study was designed to examine the effect of resveratrol, a potent activator of silent information regulator (SIRT1), on cardiac function and AMPK expression in heart failure. Adult male rat left anterior descending arteries were ligated, and they were fed with either a regular diet or a diet enriched with resveratrol. Heart failure was produced by myocardial infarction, and was associated with markedly increased AMPK and SIRT1 protein levels. Resveratrol treatment had a tremendous beneficial effect, both in terms of improving AMPK expression and on cardiac function. Decreased cardiac function and AMPK expression were also found in SIRT1 knockout (+/-) mice. In cultured cardiomyocytes, resveratrol increased AMPK and SIRT1 expressions, and overexpression of SIRT1 was found to be sufficient to activate AMPK in H9c2 cells. In contrast, pretreatment of cardiomyocytes with an SIRT1 antagonist, nicotinamide, blocked these beneficial effects of resveratrol. Therefore, the protective effects of resveratrol were found to be dependent on its ability to activate SIRT1 and improve AMPK expression. These results demonstrated that in heart failure, the enzymatic activity of cardiac SIRT1 is increased, which contributes to increased expression of AMPK, and resveratrol enhances the expression of AMPK and improves cardiac function through the activation of SIRT1.

Topics: AMP-Activated Protein Kinases; Animals; Cell Line; Cells, Cultured; Heart Failure; Male; Mice; Myocardial Infarction; Myocytes, Cardiac; Niacinamide; Rats; Resveratrol; Sirtuin 1; Stilbenes; Up-Regulation; Ventricular Function

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Animals, Newborn; Apoptosis; Autophagy; Cells, Cultured; Densitometry; Energy Metabolism; Heart Failure; Heart Function Tests; Male; Mice; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirtuin 1; Stilbenes; Superoxide Dismutase; TOR Serine-Threonine Kinases; Vacuoles; Ventricular Remodeling

We hypothesized that resveratrol administration would reverse sepsis-dependent downregulation of peroxisome proliferator activated receptor-γ coactivator 1α, preserve mitochondrial integrity, and rescue animals from sepsis-induced myocardial failure.. Teaching hospital research laboratory.. Cecal ligation and puncture in mice was performed to induce sepsis. Mice that underwent cecal ligation and puncture were randomly assigned to receive resveratrol (30 mg/kg or 60 mg/kg) or vehicle 1 mL sodium chloride 0.9% subcutaneously in the scruff of the neck directly after surgery and at 16, 24, and 40 hrs, respectively.. Forty-eight hrs after cecal ligation and puncture, cardiac performance was established using echocardiography. Mitochondrial integrity was evaluated with electron microscopy, and changes in gene expression were evaluated with microarray analysis. Survival at 48 hrs was just under 50% and comparable between groups. Myocardial contractile function significantly improved after resveratrol treatment. Resveratrol-treated mice developed focal areas of edema, whereas vehicle-treated mice developed significant, diffuse myocardial edema. Electron microscopy revealed widespread swollen mitochondria with ruptured outer membranes, autophagosomes, and vacuolation of the internal compartment, which were significantly attenuated in resveratrol-treated animals. Resveratrol treatment significantly increased cardiac expression of peroxisome proliferator-activated receptor-γ coactivator 1a. Microarray analysis revealed that resveratrol treatment resulted in upregulation of the peroxisome proliferator-activated receptor-γ coactivator gene set containing genes known to be regulated by this transcriptional coactivator. Our data strongly suggest that administration of resveratrol modulates bioenergy metabolism, substrate utilization, oxidative stress, and detoxification pathways associated with both mitochondrial and cardiac pathological conditions, but does not alter mortality from sepsis.. The salutary effects of resveratrol on cecal ligation and puncture-induced myocardial dysfunction are associated with increased peroxisome proliferator-activated receptor-γ coactivator 1a abundance and function. Preservation of myocardial energy production capacity, prevention of secondary injury, mitigation of inflammation, and reversal of sepsis-induced myocardial remodeling are likely to underlie its beneficial effects. This however, does not result in improved survival.

Topics: Animals; Cardiomyopathies; Cecum; Down-Regulation; Edema; Gene Expression; Heart Failure; Ligation; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Contraction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Resveratrol; Sepsis; Stilbenes; Trans-Activators; Transcription Factors; Vasodilator Agents

Topics: Animals; Heart Failure; Male; Myocardial Contraction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Sepsis; Stilbenes; Trans-Activators; Transcription Factors; Vasodilator Agents

To test the hypothesis that resveratrol would improve cardiac remodeling by inhibiting the detrimental effects of fractalkine. We previously reported that fractalkine exacerbates heart failure. Furthermore, this study sought to determine whether resveratrol targets fractalkine to improve myocardial ischemia and cardiac remodeling.. Randomized and controlled laboratory investigation.. Research laboratory.. Neonatal rat cardiac cells and C57BL/6 mice.. Cardiac cells were treated with recombinant mouse soluble fractalkine for 24 hrs or pretreated with 25 µM resveratrol. Cardiomyocytes were exposed to anoxia/reoxygenation, H2O2, or pretreatment with resveratrol. Ex vivo murine hearts were perfusioned with soluble fractalkine or pretreated with resveratrol after global ischemia. Mice were subjected to the left coronary artery ligation to induce myocardial infarction and randomized to treatment with resveratrol or vehicle alone for 42 days.. In a murine myocardial infarction model, we found that resveratrol increased survival and delayed the progression of cardiac remodeling evaluated by serial echocardiography. At 6 wks, the heart weight/body weight ratio, lung weight/body weight ratio, and old infarct size were significantly smaller in resveratrol-treated mice than in untreated myocardial infarction mice. In cultures of neonatal rat cells, exposure to soluble fractalkine increased the atrial natriuretic peptide expression by cardiomyocytes, matrix metalloproteinase-9 and procollagen expression by fibroblasts, and intercellular adhesion molecule-1 expression by microvascular endothelial cells, while it decreased autophagy in cardiomyocytes. All these effects were blocked by coculture with resveratrol. The methyl thiazolyl tetrazolium assay showed that soluble fractalkine reduced the viability of cultured cardiomyocytes during exposure to anoxia/reoxygenation or H2O2, while pretreatment with resveratrol blocked this effect. Perfusion of ex vivo murine hearts with soluble fractalkine after global ischemia led to an increase of infarct size, which was prevented by pretreatment with resveratrol.. Resveratrol alleviates the deleterious effects of fractalkine on myocardial ischemia and thus reduces subsequent cardiac remodeling.

Topics: Animals; Animals, Newborn; Chemokine CX3CL1; Disease Models, Animal; Electrocardiography; Heart Failure; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Platelet Aggregation Inhibitors; Random Allocation; Rats; Resveratrol; Stilbenes; Ventricular Remodeling

Topics: Animals; Chemokine CX3CL1; Heart Failure; Male; Myocardial Ischemia; Platelet Aggregation Inhibitors; Resveratrol; Stilbenes

Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening -34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium-dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

Topics: Animals; Body Weight; Disease Models, Animal; Endothelium, Vascular; Energy Metabolism; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mitochondria; Rats; Rats, Inbred Dahl; Resveratrol; Signal Transduction; Stilbenes; Survival Analysis

Topics: Animals; Antioxidants; Cardiomegaly; Cardiotonic Agents; Chronic Disease; Heart Diseases; Heart Failure; Hypertension; Myocardial Contraction; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes

Oxidative stress plays a pivotal role in chronic heart failure. SIRT1, an NAD(+)-dependent histone/protein deacetylase, promotes cell survival under oxidative stress when it is expressed in the nucleus. However, adult cardiomyocytes predominantly express SIRT1 in the cytoplasm, and its function has not been elucidated. The purpose of this study was to investigate the functional role of SIRT1 in the heart and the potential use of SIRT1 in therapy for heart failure. We investigated the subcellular localization of SIRT1 in cardiomyocytes and its impact on cell survival. SIRT1 accumulated in the nucleus of cardiomyocytes in the failing hearts of TO-2 hamsters, postmyocardial infarction rats, and a dilated cardiomyopathy patient but not in control healthy hearts. Nuclear but not cytoplasmic SIRT1-induced manganese superoxide dismutase (Mn-SOD), which was further enhanced by resveratrol, and increased the resistance of C2C12 myoblasts to oxidative stress. Resveratrol's enhancement of Mn-SOD levels depended on the level of nuclear SIRT1, and it suppressed the cell death induced by antimycin A or angiotensin II. The cell-protective effects of nuclear SIRT1 or resveratrol were canceled by the Mn-SOD small interfering RNA or SIRT1 small interfering RNA. The oral administration of resveratrol to TO-2 hamsters increased Mn-SOD levels in cardiomyocytes, suppressed fibrosis, preserved cardiac function, and significantly improved survival. Thus, Mn-SOD induced by resveratrol via nuclear SIRT1 reduced oxidative stress and participated in cardiomyocyte protection. SIRT1 activators such as resveratrol could be novel therapeutic tools for the treatment of chronic heart failure.

Topics: Adult; Animals; Cardiomyopathy, Dilated; Cell Nucleus; Cell Survival; Cells, Cultured; Chronic Disease; Cricetinae; Disease Models, Animal; Enzyme Activation; Heart Failure; Humans; Male; Mesocricetus; Mice; Muscle Fibers, Skeletal; Myocardial Infarction; Myocytes, Cardiac; Oxidative Stress; Phenols; Plant Extracts; Rats; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase

Resveratrol (RSV), a natural phenolic compound, has been found to display cardiovascular protective and insulin-sensitizing properties. In this study, the effects of RSV and its combination with insulin on mortality, hemodynamics, insulin signaling, and nitrosative stress were compared in streptozotocin (STZ)-induced diabetic rats with or without acute myocardial ischemia/reperfusion (I/R) injury. Under normoxic conditions, cardiac systolic and diastolic functions and insulin-mediated Akt/GLUT4 (glucose transporter 4) activation were impaired in STZ-diabetic rats. The combination of RSV and insulin significantly prevented the above diabetes-associated abnormalities. Notwithstanding that, the diabetic state rendered the animals more susceptible to myocardial I/R injury, and the mortality rate and inducible nitric oxide synthase (iNOS)/nitrotyrosine protein expression and superoxide anion production were also further increased in I/R-injured diabetic hearts. In contrast, RSV treatment alone resulted in a lower mortality rate (from 62.5 to 18%) and better cardiac systolic function than its combination with insulin. RSV also inhibited iNOS/nitrotyrosine protein overexpression and superoxide anion overproduction in I/R-injured diabetic myocardium. Hyperglycemia, impairment of insulin signaling, overexpression of iNOS/nitrotyrosine, and superoxide anion overproduction were markedly rescued by the combination treatment, which did not show an improvement in mortality rate (30%) or cardiac performance over RSV treatment alone. These results indicate that insulin and RSV synergistically prevented cardiac dysfunction in diabetes and this may be in parallel with activation of the insulin-mediated Akt/GLUT4 signaling pathway. Although activation of the protective signal (Akt/GLUT4) and suppression of the adverse markers (iNOS, nitrotyrosine, and superoxide anion) were simultaneously observed in insulin and RSV combination treatment, insulin counteracted the advantage of RSV in diabetics with acute heart attack.

Topics: Acute Disease; Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Heart Failure; Hemodynamics; Hypoglycemic Agents; Insulin; Male; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Streptozocin; Vasodilator Agents

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. DOX-induced heart failure is thought to be caused by reduction/oxidation cycling of DOX to generate oxidative stress and cardiomyocyte cell death. Resveratrol (RV), a stilbene found in red wine, has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to test the ability of RV to protect against DOX-induced cardiomyocyte death. We hypothesized that RV protects cardiomyocytes from DOX-induced oxidative stress and subsequent cell death through changes in mitochondrial function. DOX induced a rapid increase in reactive oxygen species (ROS) production in cardiac cell mitochondria, which was inhibited by pretreatment with RV, most likely owing to an increase in MnSOD activity. This effect of RV caused additional polarization of the mitochondria in the absence and presence of DOX to increase mitochondrial function. RV pretreatment also prevented DOX-induced cardiomyocyte death. The protective ability of RV against DOX was abolished when Sirt1 was inhibited by nicotinamide. Our data suggest that RV protects against DOX-induced oxidative stress through changes in mitochondrial function, specifically the Sirt1 pathway leading to cardiac cell survival.

Topics: Animals; Cardiotonic Agents; Cell Death; Cells, Cultured; Doxorubicin; Drug Evaluation, Preclinical; Heart Failure; Mitochondria, Heart; Myocytes, Cardiac; Niacinamide; Oxidative Stress; Rats; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Structure-Activity Relationship

To observe the protective effects of resveratrol (RES) on the heart function of the rats with adriamycin-induced heart failure.. Thirty adult male SD rats were randomly divided into 5 groups: normal control (NC) group, adriamycin (ADR) group, RESL + ADR group, RES(H) + ADR group and RES group. RES of 30, 120, 120 mg x kg(-1) x d(-1) was given intraperitoneally (ip) once a day for 3 days in RES(L) + ADR group, RES(H) + ADR group and RES group respectively. The other two groups were given the same amount of normal saline the same way. On the 4h day,ADR of 10 mg x kg(-1) was given intraperitoneally once to induce myocardium injury model. After twenty-four hours, the pathological and biochemical changes of the myocardium were examined.. As compared with NC group, the MDA, NO and NOS of the ADR group were significantly higher (P < 0.05), and the SOD of the ADR group were markedly lower (P < 0.05). As compared with ADR group, the indexes in RES(L) + ADR group, RES(H) + ADR group were exactly opposing, and took on dose dependance (P < 0.05). Light microscopic morphometry of the heart samples of the rats in ADR + RES(L, H) groups revealed typical diminishing of damage.. RES can relieve the toxic effects of ADR on myocardium, and the cardioprotective effects may be correlated with its antioxidant activity and downregulation of NO.

Topics: Animals; Doxorubicin; Heart; Heart Failure; Male; Malondialdehyde; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase