stilbenes and Myocardial-Ischemia

Cardiovascular diseases, especially ischemic heart disease and cardiometabolic disease, remain to be the leading cause of morbidity and mortality worldwide. Despite recent progress in diagnostic and therapeutic approaches, the incidence of cardiovascular disease is still rising. Therefore, alternative favorable treatment is urgently needed to rescue the fast growing numbers of patients.. Herein we aimed to review the relevant role and explore the possibility of SIRT1 as a promising target for protection of heart from ischemia/reperfusion injury and cardiometabolic diseases.. The activation of SIRT1 participates in a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance in heart ischemia injury and cardiometabolic disease.. Current medication targeting SIRT1 may represent a new therapeutic trend for the prevention of cardiovascular disease that is related to energy balance and metabolism.

Topics: Animals; Apoptosis; Disease Models, Animal; Heterocyclic Compounds, 4 or More Rings; Humans; Metabolic Diseases; Molecular Targeted Therapy; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Resveratrol; Sirtuin 1; Stilbenes; Transcriptional Activation

Until the middle of the last decade, few people had heard of microRNAs (miRNAs), 21- to 23-nucleotide conserved RNAs. MicroRNAs represent a new paradigm because they regulate most physiological processes and thus have immense potential for medical advancement. Resveratrol, a red wine-derived polyphenolic compound, has been shown to have significant effects in various disease models, such as cardioprotection in ischemic heart, diabetes, and chemoprevention of cancers. The targets of resveratrol include various pathways and molecules, such as sirtuins, FOXOs, and autophagy. The successful application of resveratrol lies in understanding its mechanisms of action through direct and indirect interactions with pathways, including miRNAs. For example, a unique miRNA footprint is present in the heart treated with resveratrol. Targets of those miRNAs have potential implications for physiological and pathophysiological processes in health and disease.

Topics: Animals; Humans; MicroRNAs; Myocardial Ischemia; Resveratrol; Stilbenes

Several experimental studies and some clinical experience have shown that metabolic syndrome and caloric restriction exert opposite effects on thrombosis, because these two nourishing conditions are at extreme ends of the same spectrum. The antithrombotic action induced by caloric restriction happens through Sirtuin 1 (SIRT1), a gene/protein activated by the reduction of calorie intake lower than is typical. The antithrombotic effect is due to the activation of SIRT1 acting through an increase of insulin sensitivity, which reduces endothelial dysfunction. Sirtuins have been implicated in several processes, including genomic stability, DNA repair, apoptosis, and adipogenesis. In addition, they have been shown to promote longevity in simple eukaryotes. Some compounds, such as resveratrol, mimic the action of SIRT1 and seem able to correct the prothrombotic state induced by metabolic syndrome. To confirm this, we demonstrated that resveratrol improved the left ventricular function of type 2 diabetics who suffered recent acute myocardial infarction (AMI) when a moderate red wine amount (containing resveratrol) was taken daily by patients receiving conventional antiischemic therapy, in comparison with another group treated with antiischemic compounds alone.

Topics: Animals; Blood Coagulation; Caloric Restriction; Fibrinolytic Agents; Humans; Metabolic Syndrome; Myocardial Ischemia; Resveratrol; Sirtuins; Stilbenes; Thrombosis; Ventricular Function, Left; Wine

The mechanisms for decreased tolerance to ischemia in the aging hearts have not been fully explored but they appear to be multifactorial. The elderly patients most often meet classification of "no-option" patients who suffer from symptoms of chronic recurrent myocardial ischemia without good options for intervention. As such these patients are in greatest need of alternative therapies for revascularization such as angiogenesis. Not only does aging and their co-morbid conditions such as hypercholesterolemia and diabetes impair the endogenous angiogenesis response but there may be decreased responsiveness to exogenous angiogenic therapies. Enhancing the effectiveness of angiogenic therapy in this ever increasing subgroup of cardiovascular patients is as yet unmet. One such promising avenue involves sirtuins. Herein, we review the effect of aging on the processes of angiogenesis and explore the implications for successful clinical treatment of myocardial ischemia with angiogenesis therapy, with particular focus on modification of sirtuins and their targets by resveratrol along with some recent patents.

Topics: Aging; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Collateral Circulation; Coronary Vessels; Humans; Myocardial Ischemia; Resveratrol; Sirtuins; Stilbenes

The polyphenolic compound resveratrol presented in red wine has potent cardiovascular effect in animal. Here, we investigated the ability of resveratrol to relax human coronary bypass grafts, saphenous vein and internal mammary artery and also its effect on their endothelial reactivity.. Vascular rings were obtained from 38 male patients undergoing coronary artery bypass operation. The relaxant effects of resveratrol (10-70 microM) and acetylcholine (10(-8)-10(-4) M) were examined on precontracted saphenous vein and internal mammary artery rings.. Resveratrol, at concentration of 70 microM caused relaxations of 34.2+/-5.7% in saphenous vein and 35.2+/-5.4% in internal mammary artery. Endothelium removal and l-NOARG (nitric oxide synthase inhibitor, 10(-4) M) pretreatment almost completely inhibited the relaxation to resveratrol in internal mammary artery but partially in saphenous vein rings. Indomethacin (cyclooxygenase inhibitor, 10(-5) M) slightly, but not significantly enhanced the relaxation to resveratrol in both vessels. The endothelium-dependent relaxations to acetylcholine were significantly improved in the presence of resveratrol of 20 microM in both grafts (E(max): 33.8+/-3.7% versus 46.8+/-4% in saphenous vein n=9; p<0.05; 54. 4+/-5.3% versus 69.3+/-5.4% in internal mammary artery, n=8, p<0.05). The relaxations to acetylcholine were fully eliminated by combination of resveratrol with l-NOARG (10(-4) M) in both vessels.. Resveratrol produced mainly endothelium-dependent and nitric oxide-mediated vasodilation in human internal mammary artery but partially in saphenous vein rings and improved their endothelial reactivity. This may have a therapeutic potential in cardiovascular diseases.

Topics: Acetylcholine; Antioxidants; Coronary Artery Bypass; Endothelium, Vascular; Female; Follow-Up Studies; Humans; In Vitro Techniques; Indomethacin; Male; Mammary Arteries; Middle Aged; Myocardial Ischemia; Norepinephrine; Resveratrol; Saphenous Vein; Stilbenes; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Grape pomace is a potential source of natural antioxidant agents. Phenolic compounds and antioxidant and cardioprotective properties of fresh and fermented pomace extracts obtained from

Topics: Animals; Anthocyanins; Antioxidants; Cardiotonic Agents; Chromatography, High Pressure Liquid; Flavonoids; Isoproterenol; Male; Malondialdehyde; Myocardial Ischemia; Nitrates; Oxidative Stress; Plant Extracts; Polyphenols; Proanthocyanidins; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization; Stilbenes; Vitis

Epidemiological studies strongly suggest a link between stress, depression, and cardiovascular diseases (CVDs); the mechanistic correlation, however, is poorly understood. A single-nucleotide polymorphism in the BDNF gene (BDNFVal66Met), associated with depression and anxiety, has been proposed as a genetic risk factor for CVD. Using a knock-in mouse carrying the BDNFVal66Met human polymorphism, which phenocopies psychiatric-related symptoms found in humans, we investigated the impact of this SNP on thrombosis.. BDNFMet/Met mice displayed a depressive-like phenotype concomitantly with hypercoagulable state and platelet hyperreactivity. Proteomic analysis of aorta secretome from BDNFMet/Met and wild-type (WT) mice showed differential expression of proteins involved in the coagulation and inflammatory cascades. The BDNF Met allele predisposed to carotid artery thrombosis FeCl3-induced and to death after collagen/epinephrine injection. Interestingly, transfection with BDNFMet construct induced a prothrombotic/proinflammatory phenotype in WT cells. SIRT1 activation, using resveratrol and/or CAY10591, prevented thrombus formation and restored the physiological levels of coagulation and of platelet markers in BDNFMet/Met mice and/or cells transfected with the Met allele. Conversely, inhibition of SIRT1 by sirtinol and/or by specific siRNA induced the prothrombotic/proinflammatory phenotype in WT mice and cells. Finally, we found that BDNF Met homozygosity is associated with increased risk of acute myocardial infarction (AMI) in humans.. Activation of platelets, alteration in coagulation pathways, and changes in vessel wall protein expression in BDNFMet/Met mice recapitulate well the features occurring in the anxiety/depression condition. Furthermore, our data suggest that the BDNFVal66Met polymorphism contribute to the individual propensity for arterial thrombosis related to AMI.

Topics: Animals; Anxiety Disorders; Aorta; Blood Coagulation; Brain-Derived Neurotrophic Factor; Carotid Arteries; Carotid Artery Thrombosis; Depressive Disorder; Disease Models, Animal; Female; Heterozygote; Homozygote; Humans; Male; Mice, Transgenic; Middle Aged; Myocardial Ischemia; Nerve Tissue Proteins; Platelet Activation; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Thrombosis

Resveratrol has been shown to improve cardiac perfusion and ventricular function after chronic ischemic injury. Using proteomic analysis, we sought to objectively investigate potential mechanisms, by which resveratrol exerts its cardioprotective effects in the setting of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were divided into two groups based on diet: high cholesterol (n=7) or a high-cholesterol diet with supplemental resveratrol (n=6). Four weeks later, all animals underwent surgical placement of an ameroid constrictor to their left circumflex artery. Diets were continued for another 7 weeks, and then the ischemic myocardium was harvested for proteomics analysis. Proteomic analysis identified 669 common proteins between the two groups. Of these proteins, 76 were statistically different, of which 41 were characterized (P<.05). Pathway analysis demonstrated that in animals supplemented with resveratrol, there was a downregulation in several proteins involved with mitochondrial dysfunction, cell death, and unfavorable cardiac remodeling. Furthermore, there was an upregulation in proteins involved in free radical elimination. We conclude that resveratrol supplementation significantly alters several critical protein markers in the chronically ischemic myocardium. Further investigation of these proteins may help elucidate the mechanisms by which resveratrol exerts its cardioprotective effects.

Topics: Animals; Antioxidants; Biomarkers; Cell Death; Cholesterol, Dietary; Coronary Vessels; Dietary Supplements; Disease Models, Animal; Heart; Male; Metabolic Syndrome; Mitochondria; Myocardial Ischemia; Myocardium; Phytotherapy; Plant Extracts; Proteins; Proteomics; Resveratrol; Signal Transduction; Stilbenes; Swine

Autophagy is a cellular process by which damaged components are removed. Although autophagy can result in cell death, when optimally regulated, it might be cardioprotective. Resveratrol is a naturally occurring polyphenol also believed to be cardioprotective. Using a clinically relevant swine model of metabolic syndrome, we investigated the effects of resveratrol on autophagy in the chronically ischemic myocardium.. Yorkshire swine were fed a regular diet (n = 7), a high cholesterol diet (n = 7), or a high cholesterol diet with supplemental resveratrol (n = 6). After 4 weeks, an ameroid constrictor was surgically placed on the left circumflex artery to induce chronic myocardial ischemia. The diets were continued another 7 weeks, and then the ischemic and nonischemic myocardium were harvested for protein analysis.. In the ischemic myocardium, a high cholesterol diet partly attenuated the autophagy, as determined by an increase in phosphorylated mammalian target of rapamycin (p-mTOR) and a decrease in p70 S6 kinase (P70S6K), lysosome-associated membrane protein (LAMP)-2, and autophagy-related gene 12-5 conjugate (ATG 12-5; P < .05). The addition of resveratrol blunted many of these changes, because the p-mTOR, P70S6K, and LAMP-2 levels were not significantly altered from those of the pigs fed a regular diet. Other autophagy markers were increased with a high cholesterol diet, including light chain 3A-II and beclin 1 (P < .05). In the nonischemic myocardium, beclin 1 was decreased in the high cholesterol-fed pigs (P < .05); otherwise no significant changes in protein expression were noted among the 3 groups.. In the chronically ischemic myocardium, resveratrol partly reversed the effects of a high cholesterol diet on autophagy. This might be a mechanism by which resveratrol exerts its cardioprotective effects.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Blotting, Western; Cholesterol, Dietary; Diet, High-Fat; Disease Models, Animal; Lysosomal-Associated Membrane Protein 2; Male; Microtubule-Associated Proteins; Myocardial Ischemia; Myocardium; Phosphorylation; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Stilbenes; Swine; Swine, Miniature; Time Factors; TOR Serine-Threonine Kinases

It was proposed that resveratrol, a polyphenolic antioxidant and a calorie restriction mimetic could promote longevity but subsequent studies could not prove this. The original proposal was based on the fact that a grape-derived antioxidant could activate the antiaging gene Sirt1. Most studies agree that indeed grape activates Sirt1, but a question remains whether Sirt1 is the cause or consequence of resveratrol treatment. Subsequently, mitochondrial Sirt3 was found to be activated. The present study on ischemic reperfusion (I/R) in rat hearts demonstrates that Foxo3a is activated subsequent to Sirt3 activation, which then activates PINK1. PINK1 potentiates activation of PARKIN leading to the activation of mitochondrial fission and mitophagy. Confocal microscopy conclusively shows the coexistence of Sirt3 with Foxo3a and Foxo3a with PINK1 and PARKIN. Mitophagy was demonstrated both by confocal microscopy and transmission electron microscopy. Western blot analyses data are consistent with the results of confocal microscopy. It appears that the grape-derived antioxidant modifies the intracellular environment by changing the oxidizing milieu into a reducing milieu and upregulating intracellular glutathione, potentiates a signal transduction cascade consisting of Sirt1/Sirt3-Foxo3a-PINK1-PARKIN-mitochondrial fusion fission-mitophagy that leads to cardioprotection, and paves the way to an anti-aging environment.

Topics: Aging; Animals; Antioxidants; Apoptosis; Blotting, Western; Fluorescent Antibody Technique; Forkhead Box Protein O3; Forkhead Transcription Factors; Glutathione; Heart Ventricles; In Vitro Techniques; Intracellular Space; Male; Mitochondrial Dynamics; Mitophagy; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Protein Kinases; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Signal Transduction; Sirtuins; Stilbenes; Ubiquitin-Protein Ligases; Vitis

Resveratrol is a naturally occurring polyphenol believed to be cardioprotective. We previously demonstrated that resveratrol improves insulin signaling and glucose metabolism in liver and skeletal muscle of swine with metabolic syndrome. Although resveratrol has metabolic benefits in peripheral tissues, its effect on insulin signaling in ischemic myocardium (IM) is unclear. Therefore, we developed a clinically relevant swine model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of resveratrol on insulin signaling in cardiac tissue.. Thirteen male Yorkshire swine were fed a high-cholesterol diet for 4 wk then underwent surgical placement of an ameroid constrictor to their circumflex artery to induce chronic myocardial ischemia. The high-cholesterol control group was given no drug (n = 7). The experimental group was provided the same diet and received supplemental resveratrol (100 mg/kg/d) (n = 6). Tissue was harvested 7 wk after ameroid placement for western blot and histological analyses.. In IM, there was no significant difference between the two groups in the insulin signaling markers studied. In nonischemic myocardium, there was a significant decrease in phosphorylated AMP-activated protein kinase α (P = 0.021) in the group treated with resveratrol; otherwise, there were no significant differences between the groups. Immunostaining for glucose transporter 4 and Periodic acid-Schiff staining for myocardial glycogen stores was similar between the groups.. Resveratrol has complex effects on glucose metabolism. Although prior studies demonstrated that resveratrol supplementation improves insulin sensitivity in peripheral tissues, in chronically IM, there are no significant alterations.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cardiotonic Agents; Disease Models, Animal; Glucose; Insulin; Male; Metabolic Syndrome; Myocardial Ischemia; Myocardium; Resveratrol; Signal Transduction; Stilbenes; Swine

Resveratrol, a constituent of red wine, and γ-tocotrienol, a constituent of palm oil are important for cardioprotection. Although microRNAs are known regulators for genes involved in cardiac remodelling, the regulatory pathway involving microRNA has not been studied so far. We explored the cardioprotection by resveratrol, longevinex and γ-tocotrienol in ischaemia/reperfusion(I/R) model of rat and determined miRNA profile from isolated RNA. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches. Resveratrol and γ-tocotrienol, either alone or in combination, modulated the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 75 miRNAs, some of them, such as miR-21 and miR-20b (anti-angiogenic) were previously implicated in cardiac remodelling. The target genes for the highest differentially expressed miRNA include genes of various molecular functions such as TGFβ1-Smad3 signalling pathway, inflammation and their transcription factors, which may play key role in reducing I/R injury. Administration of antagomiR-20 attenuated I/R induced vascular endothelial growth factor and HIF1α level. All the interventions treated for 3 weeks lead to significant cardioprotection against ischaemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or γ-tocotrienol. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R rat. Interestingly, resveratrol and γ-tocotrienol resulted in synergestic action.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Chromans; Down-Regulation; Drug Synergism; Gene Expression Profiling; Heart; Hypoxia-Inducible Factor 1, alpha Subunit; Male; MicroRNAs; Microscopy, Confocal; Multivariate Analysis; Myocardial Ischemia; Myocardium; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes; Vascular Endothelial Growth Factor A; Vitamin E

Resveratrol has been shown to reverse some of the detrimental effects of metabolic syndrome (MetS). We sought to define the impact of supplemental resveratrol on normal myocardium remote from an ischemic territory in a swine model of MetS and chronic myocardial ischemia.. Yorkshire swine were fed a normal diet (control), a high cholesterol diet (HCD), or a high cholesterol diet with orally supplemented resveratrol (HCD-R; 100 mg/kg/day). Four weeks after diet modification, myocardial ischemia was induced by ameroid constrictor placement. Seven weeks later, myocardial tissue from a territory remote from the ischemia was harvested. Animals in the HCD and HCD-R groups underwent functional cardiac MRI before ischemia and before sacrifice. Tissue was harvested for protein expression analysis.. After 7 weeks of ischemia, regional left ventricular systolic function was significantly increased in HCD-R as compared with HCD animals. During ventricular pacing the HCD group had significantly decreased flow (p = 0.03); perfusion in the HCD-R was preserved as compared with the control. There was no difference in microvascular relaxation. Expression of metabolic proteins Sirt-1 (p = 0.002), AMPkinase (p = 0.02), and carnitine palmitoyltransferase-I (p = 0.002) were upregulated in the HCD-R group. Levels of protein oxidative stress were significantly increased in the HCD and HCD-R groups, as compared with the controls (p = 0.003). Activated endothelial nitric oxide synthase (eNOS) was increased in the HCD-R group (p = 0.01). There was no difference in myocardial endothelial cell density between the groups; however, dividing endothelial cells were decreased in the HCD and HCD-R groups (p = 0.006).. Resveratrol supplementation improves regional left ventricular function and preserves perfusion to myocardium remote from an area of ischemia in an animal model of metabolic syndrome and chronic myocardial ischemia.

Topics: Animals; Antioxidants; Biomarkers; Blotting, Western; Coronary Vessels; Diet, High-Fat; Disease Models, Animal; Fluorescent Antibody Technique; Heart; Magnetic Resonance Imaging; Metabolic Syndrome; Myocardial Ischemia; Myocardium; Oxidative Stress; Resveratrol; Stilbenes; Swine; Ventricular Function, Left

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

The present study examined the efficacy of using longevinex, a commercially available resveratrol formulation, to lower blood cholesterol in hypercholesteromic rabbits. New Zealand white rabbits were randomly divided into two groups (n = 6 per group), one group was given high cholesterol diet for 3 months while the other group fed regular diet served as control. The high cholesterol diet fed group was further subdivided into two groups (n = 6 per group), one group was given longevinex resveratrol while the other group given vehicle only served as control. Longevinex was given by gavaging up to a period of 6 months. Longevinex-treated rabbits exhibited lowering of plasma cholesterol level. Inhibition of arterial plaque formation was noticed even after 1 month. Longevinex-treated hearts demonstrated improved ventricular recovery when isolated working hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. Aortic flow and developed pressure during post-ischemic reperfusion period were significantly higher for the longevinex-treated hearts compared to those in control group of hearts. Myocardial infarct size was also lower in the treated group compared to that for the untreated group. These results indicate cholesterol-lowering ability of longevinex, which appears to reflect in its ability to protect the hypercholesteromic hearts from ischemic reperfusion injury.

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Biomarkers; Cholesterol; Disease Models, Animal; Down-Regulation; Hemodynamics; Hypercholesterolemia; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rabbits; Resveratrol; Stilbenes; Time Factors; Ventricular Function, Left; Ventricular Pressure

Resveratrol has been purported to modify risk factors for obesity and cardiovascular disease. We sought to examine the effects of resveratrol in a porcine model of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were fed either a normal diet (control), a high cholesterol diet (HCD), or a high cholesterol diet with supplemental resveratrol (HCD-R; 100mg/kg/day) for 11 weeks. After 4 weeks of diet modification a baseline cardiovascular MRI was performed and an ameroid constrictor was placed on the left circumflex coronary artery of each animal to induce chronic myocardial ischemia. At 7 weeks, a second cardiovascular MRI was performed and swine were sacrificed and myocardial tissue harvested. Resveratrol supplementation resulted in lower body mass indices, serum cholesterol, and C-reactive protein levels, improved glucose tolerance and endothelial function, and favorably augmented signaling pathways associated with myocardial metabolism. Interestingly, serum tumor necrosis factor-α levels were not influenced by resveratrol treatment. Immunoblotting for markers of metabolism demonstrated that insulin receptor substrate-1, glucose transporters 1 and 4, and phospho-AMPK were increased in the HCD-R group. Peroxisome proliferator-activated receptor γ and retinol binding protein 4 were downregulated in the HCD-R group as compared to the HCD group. Myocardial perfusion and function at rest as assessed with magnetic resonance imaging were not different between groups. By favorably influencing risk factors, resveratrol may decrease the burden of chronic metabolic disease and improve cardiovascular health.

Topics: Animals; Biomarkers; Cholesterol; Coronary Artery Disease; Diet; Dietary Supplements; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucose Tolerance Test; Glucose Transporter Type 4; Heart; Inflammation; Insulin; Magnetic Resonance Imaging; Metabolic Syndrome; Microvessels; Muscle Cells; Myocardial Ischemia; Oxidation-Reduction; Protein Transport; Resveratrol; Risk Factors; Stilbenes; Swine

Clinical trials of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) have been disappointing, owing likely to endothelial dysfunction. We used a swine model of chronic ischemia and endothelial dysfunction to determine whether resveratrol coadministration would improve the angiogenic response to VEGF therapy.. Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement, and were given either no drug (high cholesterol control [HCC], n = 8), perivascular VEGF (2 μg sustained release [high cholesterol VEGF-treated; HCV], n = 8), or VEGF plus oral resveratrol (10 mg/kg, [high cholesterol VEGF- and resveratrol-treated; HCVR], n = 8). After 7 weeks, myocardial contractility, perfusion, and microvessel reactivity in the ischemic territory were assessed. Tissue was analyzed for vessel density, oxidative stress, and protein expression.. Myocardial perfusion was significantly improved in the HCV group compared with the HCC group; resveratrol coadministration abrogated this improvement. There were no differences in regional myocardial contractility between groups. Endothelium-dependent microvessel relaxation was improved in the HCVR group, and endothelium-independent relaxation response was similar between groups. Arteriolar density was greatest in the HCV group, whereas capillary density was similar between groups. Expression of Akt and phospho-endothelial nitric oxide synthase were increased in the HCVR group. Total protein oxidative stress and myeloperoxidase expression were reduced in the HCVR group, but so was the oxidative-stress dependent phosphorylation of vascular endothelial cadherin (VE-cadherin) and β-catenin.. Although resveratrol coadministration decreases oxidative stress and improves endothelial function, it abolishes improvements in myocardial perfusion and arteriolar density afforded by VEGF treatment alone. This effect is due likely to inhibition of the oxidative stress-dependent phosphorylation of VE-cadherin, an essential step in the initiation of arteriogenesis.

Topics: Administration, Oral; Animals; Blood Chemical Analysis; Coronary Angiography; Coronary Circulation; Disease Models, Animal; Drug Therapy, Combination; Hypercholesterolemia; Immunoblotting; Immunohistochemistry; Male; Myocardial Ischemia; Neovascularization, Physiologic; Oxidative Stress; Phosphorylation; Random Allocation; Reference Values; Resveratrol; Risk Factors; Sensitivity and Specificity; Stilbenes; Swine; Vascular Endothelial Growth Factor A

Resveratrol has been reported to induce angiogenesis in ischemic tissue. We hypothesized that high-dose resveratrol would improve native angiogenesis in a swine model of metabolic syndrome and chronic myocardial ischemia.. Yorkshire swine were fed a normal diet (Control, n = 7), hypercholesterolemic diet (HCD, n = 7), or hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/day orally, HCD-R; n = 7) beginning 1 month prior to surgery. Chronic ischemia was created by placing an ameroid constrictor on the left circumflex coronary artery. After 7 weeks, swine underwent functional MRI, coronary angiography, and serum and heart tissue harvest for analysis.. HCD-R animals had lower body mass index (P < .001), total cholesterol (P < .001), low-density lipoprotein (LDL; P < .001), blood glucose levels (P < .001), and systolic blood pressure (P = .03) than HCD animals. There was no difference in regional myocardial function at 7 weeks (P = .25). Coronary angiograms revealed no difference in Rentrop collateral scores (P = .68). Staining for platelet endothelial cell adhesion molecule-1 demonstrated higher capillary density in the Control group (versus HCD and HCD-R; P = .02). Immunoblotting demonstrated decreased expression of the pro-angiogenic protein vascular endothelial (VE)-cadherin (P = .002) and an increase in anti-angiogenic proteins angiostatin (P = .001) and thrombospondin (P = .02) in the HCD and HCD-R groups. Matrix metalloprotease 2 (MMP 2; P = .47) and MMP 9 (P = .12) were not different among groups.. Supplemental resveratrol positively modified cardiovascular risk factors including body mass index, cholesterol, glucose tolerance, and systolic blood pressure. However, it did not increase native collateral formation in the ischemic myocardium. This may be a result of increased angiostatin and thrombospondin leading to decreased expression of VE-cadherin and other pro-angiogenic factors.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Antigens, CD; Cadherins; Cholesterol, Dietary; Collateral Circulation; Coronary Angiography; Disease Models, Animal; Magnetic Resonance Imaging; Male; Metabolic Syndrome; Myocardial Ischemia; Neovascularization, Physiologic; Resveratrol; Stilbenes; Swine; Swine, Miniature

Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway.. Ischemic AMPK activation was impaired in aged compared with young murine hearts. The expression and secretion of the AMPK upstream regulator, macrophage migration inhibitory factor (MIF), were lower in aged compared with young adult hearts. Additionally, the levels of hypoxia-inducible factor 1alpha, a known transcriptional activator of MIF, were reduced in aged compared with young hearts. Ischemia-induced AMPK activation in MIF knockout mice was blunted, leading to greater contractile dysfunction in MIF-deficient than in wild-type hearts. Furthermore, intramyocardial injection of adenovirus encoding MIF in aged mice increased MIF expression and ischemic AMPK activation and reduced infarct size.. An impaired MIF-AMPK activation response in senescence thus may be attributed to an aging-associated defect in hypoxia-inducible factor 1alpha, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1alpha activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients.

Topics: Aging; AMP-Activated Protein Kinases; Animals; Down-Regulation; Enzyme Inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Mice; Mice, Knockout; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Phenotype; Phosphorylation; Resveratrol; Signal Transduction; Stilbenes; Ultrasonography; Ventricular Function, Left

Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia.. Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (P<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (P=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (P=0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine (P=0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment (P=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine (P=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF (P=0.002), peNOS (ser1177) (P=0.04), NFkB (P=0.004), and pAkt (thr308) (P=0.001).. Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Capillaries; Chronic Disease; Coronary Circulation; Coronary Disease; Disease Models, Animal; Female; Humans; Hypercholesterolemia; Male; Microcirculation; Myocardial Ischemia; Myocardium; Neovascularization, Physiologic; Perfusion; Resveratrol; Signal Transduction; Stilbenes; Swine; Vascular Endothelial Growth Factor A

Resveratrol, a constituent of red wine, is important for cardioprotection. MicroRNAs are known regulators for genes involved in resveratrol-mediated cardiac remodeling and the regulatory pathway involving microRNA has not been studied so far.. We explored the cardioprotection by resveratrol in ischemia/reperfusion model of rat and determined cardiac functions. miRNA profile was determined from isolated RNA using quantitative Real-time PCR based array. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches.. Cardioprotection by resveratrol and its derivative in ischemia/reperfusion [I/R] rat model was examined with miRNA expression profile. Unique expression pattern were found for each sample, particularly with resveratrol [pure compound] and longevinex [commercial resveratrol formulation] pretreated hearts. Longevinex and resveratrol pretreatment modulates the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 25 miRNAs, some of them, such as miR-21 were previously implicated in cardiac remodeling. The target genes for the differentially expressed miRNA include genes of various molecular function such as metal ion binding, sodium-potassium ion, transcription factors, which may play key role in reducing I/R injury.. Rats pretreated with resveratrol for 3 weeks leads to significant cardioprotection against ischemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or longevinex. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R mice.

Topics: Animals; Cardiotonic Agents; Computational Biology; Heart; Male; Mice; MicroRNAs; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Software; Stilbenes

Recent studies have demonstrated the cardioprotective abilities of resveratrol, a polyphenolic antioxidant present in red wine. Resveratrol can also kill cancer cells at relatively higher doses by exerting a death signal. We reasoned that resveratrol might possess the ability to protect the cells at lower doses as observed during pharmacological preconditioning of the heart, while at higher doses cause cell death as found for cancer cells. To test this hypothesis, rats were randomly fed for 14 days by gavaging any of the four doses of resveratrol - 2.5, 5.0, 25 or 50 mg/kg - while vehicle-fed animals served as placebo control. After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The rats fed either 2.5 or 5 mg/kg dose of resveratrol for 14 days provided cardioprotection as evidenced by improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis compared to control. In contrast, the hearts fed either 25 or 50 mg/kg dose of resveratrol depressed cardiac function and increased myocardial infarct size and number of apoptotic cells. The results for Western blots and RT-PCR demonstrated an increase of protein and RNA transcripts of redox proteins including thioredoxin (Trx)-1, Trx-2, glutaredoxin (Grx)-1, Grx-2, redox factor Ref-1 as well as redox-sensitive transcription factor NFkappaB, and survival factors such as phosphorylated-Akt (p-Akt), and Bcl-2 in the animals fed lower doses (2.5 and 5 mg/kg) of resveratrol, while the reverse was true for the animals fed higher doses (25 and 50 mg/kg) of resveratrol. The results thus indicate that at lower doses (2.5 or 5 mg/kg), resveratrol exerts survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Male; Myocardial Ischemia; NF-kappa B; Oxidation-Reduction; Phytoalexins; Rats; Rats, Sprague-Dawley; Resveratrol; Sesquiterpenes; Signal Transduction; Stilbenes; Terpenes; Wine

Loss of cardiomyocytes through apoptosis has been proposed as a cause of ventricular remodeling and heart failure. Ischemia- and hypoxia-induced apoptosis of cardiomyocytes reportedly plays an important role in many cardiac pathologies. We investigated whether resveratrol (Res) has direct cytoprotective effects against ischemia/hypoxia for cardiomyocytes. Exposure of H9c2 embryonic rat heart-derived cells to hypoxia for 24h caused a significant increase in apoptosis, as evaluated by TUNEL and flow cytometry, while treatment with 20 microM Res greatly decreased hypoxia-induced apoptosis in these cells. Exposure of the cells to Res (20 microM) caused rapid activation of SIRT1, which had a dual effect on FoxO1 function: SIRT1 increased FoxO1's ability to induce cell cycle arrest, but inhibited FoxO1's ability to induce cell death. This effect could be reversed by SIRT1 inhibition. Results of our study indicate that Res inhibits hypoxia-induced apoptosis via the SIRT1-FoxO1 pathway in H9c2 cells. This polyphenol may have potential in preventing cardiovascular disease, especially in coronary artery disease (CAD) patients.

Topics: Animals; Antioxidants; Apoptosis; Cell Hypoxia; Cells, Cultured; Cytoprotection; Forkhead Transcription Factors; Myocardial Ischemia; Myocytes, Cardiac; Nerve Tissue Proteins; Rats; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

The purpose of this study was to investigate the effect of resveratrol, a polyphenol present in grapes and red wine, on ventricular remodeling after myocardial infarction (MI) in rats. After permanent ligation of the left anterior descending artery, surviving rats were randomly allocated to three groups and treated with 1 mg/kg/day resveratrol (R-1 group), 0.1 mg/kg/day resveratrol (R-0.1 group), or vehicles (control group) administered by intraperitoneal injection once daily for four weeks. We examined the effects of resveratrol by echocardiography, hemodynamic studies, histologic examinations, and real-time quantitative polymerase chain reaction. The R-1 group had significantly increased fractional shortening of the left ventricle, ameliorated left ventricular dilatation, reduced left ventricular end-diastolic pressure, and reduced infarct size. In contrast, the R-0.1 group experienced no beneficial effects on myocardial infarction. The R-1 group also had significantly attenuated expression of myocardial atrial natriuretic peptide and transforming growth factor-beta1 mRNAs. This study indicates that resveratrol is a potent cardioprotective agent in MI rats. Its cardioprotective effects may be due to a reduction of atrial natriuretic peptide and transforming growth factor-beta1, which are known to protect the heart from detrimental remodeling.

Topics: Animals; Antioxidants; Atrial Natriuretic Factor; Collagen Type I; Echocardiography; Hemodynamics; Male; Mice; Myocardial Ischemia; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Transforming Growth Factor beta1; Ventricular Remodeling

It is generally believed that the French paradox is related to the consumption of red wine and not other varieties of wine, including white wine or champagne. Some recent studies have indicated that white wine could also be as cardioprotective as red wine. The present investigation compares the cardioprotective abilities of red wine, white wine, and their principal cardioprotective constituents. Different groups of rats were gavaged with red wine, white wine, resveratrol, tyrosol, and hydroxytyrosol. Red wine and its constituent resveratrol and white wine and its constituents tyrosol and hydroxytyrosol all showed different degrees of cardioprotection as evidenced by their abilities to improve postischemic ventricular performance, reduce myocardial infarct size and cardiomyocyte apoptosis, and reduce peroxide formation. It was discovered in this study that although each of the wines and their components increased the enzymatic activities of the mitochondrial complex (I-IV) and citrate synthase, which play very important roles in oxidative phosphorylation and ATP synthesis, some of the groups were more complex-specific in inducing the activity compared to the other groups. Cardioprotective ability was further confirmed by increased expression of phospho-Akt, Bcl-2, eNOS, iNOS, COX-1, COX-2, Trx-1, Trx-2, and HO-1. The results of this study suggest that white wine can provide cardioprotection similar to red wine if it is rich in tyrosol and hydroxytyrosol.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Cardiotonic Agents; Heart; Humans; In Vitro Techniques; Male; Mitochondrial Swelling; Myocardial Ischemia; Myocardium; Peroxides; Phenylethyl Alcohol; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Wine

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a naturally occurring polyphenolic compound found abundantly in grape skins and red wines, has been found to pharmacologically precondition the heart against ischemia reperfusion injury through the potentiation of a survival signal involving cAMP response element-binding protein-dependent phosphatidylinositol 3-kinase-Akt-BclII pathway. The present study was designed to determine whether, similar to ischemic preconditioning, resveratrol uses mitogen-activated protein kinases (MAPKs) as upstream signaling targets. The isolated rat hearts were preperfused for 15 min with Krebs-Henseleit bicarbonate buffer in the absence (control) or presence of extracellular signal-regulated kinase (ERK) 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059), p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB-202190), mitogen- and stress-activated protein kinase 1 (MSK-1) inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), protein kinase A inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3fg: 3',2',1'-kl]-pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT5720), resveratrol only, resveratrol plus PD98059, resveratrol plus SB-202190, resveratrol plus H89, or resveratrol plus KT5720. Consistent with previous reports, resveratrol provided cardioprotection as evidenced by its ability to improve postischemic ventricular function, reduction of myocardial infarct size, and cardiomyocyte apoptosis. The cardioprotection afforded by resveratrol was partially abolished with PD98059 or SB-202190, suggesting that ERK1/2 and p38 MAPK play roles in resveratrol-mediated preconditioning. An MSK-1 inhibitor, H89, abolished resveratrol-mediated preconditioning, indicating MSK-1 to be the downstream target molecule for both ERK1/2 and p38 MAPK. KT5720 had no effect on resveratrol-mediated cardioprotection. Corroborating these results, Western blot analysis revealed phosphorylation of ERK1/2, p38 MAPK, MAPK-activated protein (MAPKAP) kinase 2, and MSK-1 with resveratrol and inhibition of phosphorylation with corresponding inhibitors. These results showed for the first time that resveratrol triggers an MAPK signaling pathway involving ERK1/2 and p38 MAPK, the former using MSK-1 as the downstream target and the latter, using both MAPKAP kinase 2 and MSK-1 as downstream targets.

Topics: Animals; Cardiotonic Agents; Cyclic AMP Response Element-Binding Protein; Enzyme Inhibitors; In Vitro Techniques; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Ischemia; Myocardium; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes

The major objective of the present study was to examine the cardioprotective effect of resveratrol, an antioxidant presents in red wine, in the rat after ischemia-reperfusion (I/R).. The left coronary artery was in occlusion for 30 min followed by a 120 min reperfusion in anesthetized rats. Animals were pretreated with and without resveratrol before occlusion. The post-ischemic ventricular function (left ventricle maximum systolic pressures and the maximal first derivative of developed pressure) and myocardial infarct size and myocardial nitric oxide (NO) and malonaldehyde (MDA) content were compared.. Resveratrol pretreatment had dramatic cardioprotective effects on post-ischemic ventricular functional recovery and decreasing myocardial infarct size. Resveratrol pretreatment also increased NO and decreased MDA content in myocardium.. Resveratrol has cardioprotective properties in I/R rats. The cardioprotective effects in the I/R rats may be correlated with its antioxidant activity and upregulation of NO production.

Topics: Animals; Antioxidants; Cardiotonic Agents; Free Radical Scavengers; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Up-Regulation

We have recently demonstrated the cardioprotective effects of a non-alcoholic extract of Argentinian red wine (RWE) on ischemia-reperfusion injury. The aim of the present study was to assess the relative contribution of four phenolic fractions separated from RWE by liquid/liquid extraction with solvents of decreasing hydrophobicity, to the myocardial protection achieved by the original extract. Isovolumic perfused rat hearts treated with each fraction 10 min before ischemia and the first 10 min of reperfusion were submitted to a 20-min global ischemic period followed by 30 min of reperfusion. The treatment with the fraction rich in polymeric proanthocyanidins (fraction IV = aqueous residue) significantly improved the postischemic recovery of left ventricular developed pressure (LVDP) and +dP/dt (max) (111 +/- 5% and 117 +/- 6% vs 61 +/- 4%, 62 +/- 5% , respectively, detected in control hearts) and abolished the increase of left ventricular end diastolic pressure (LVEDP) (8 +/- 2 mmHg vs 42 +/- 4 mmHg in untreated hearts). However, the fraction rich in anthocyanins (III: butanol) elicited a cardioprotective action weaker than the original extract. On the other hand, the representative of either resveratrol or flavan-3-ols and flavonols (fractions I and II) failed to induce this type of response. LDH release and TBARS concentration were significantly lowered after treatment with fraction IV alone. These data show that the fraction rich in polymeric proanthocyanidins exerts a protective effect against myocardial alterations derived from ischemia and reperfusion comparable to the original RWE. This beneficial effect can be correlated to the ability of that fraction to attenuate the degree of lipid peroxidation.

Topics: Animals; Argentina; Blood Pressure; Cardiotonic Agents; Flavonols; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Phenols; Rats; Rats, Wistar; Resveratrol; Stilbenes; Thiobarbituric Acid Reactive Substances; Ventricular Function, Left; Wine

The major objective of the present study is to evaluate the potential role of resveratrol (RVT), a natural antioxidant found in grapes and red wine, in protecting the myocardium from the deleterious effects of ischemia-reperfusion (I/R) injury using isolated rat hearts.. Langendorff perfused isolated rat hearts were subjected to 60 min of global ischemia following 60 min of reperfusion. RVT was given according to chronic pretreatment and/or acute treatment protocols. Animals received RVT at the dose of 20 mg/kg via an intragastric tube for 14 days before the experiment and/or at the infusion concentration of 10 microM for 30 min before the onset of ischemia. The myocardial postischemic recovery was compared using hemodynamic data (peak systolic pressure, end diastolic pressure, and +dP/dtmax), coronary flow, biochemical parameters (LDH, CK-MB, cTnI, myoglobin) from coronary effluent, and oxidative stress markers (MDA, GSH, carbonyl) from heart tissue homogenates in each group.. RVT pretreatment and treatment protocols have provided increased preservation in myocardial recovery following global ischemia compared to a non-treated group. Furthermore, the ischemic damage of myocardium was significantly lower in chronic pretreated rats than in the acutely treated group. In contrast, no significant difference was observed in cardioprotective effects of RVT between the only pretreated group, and both the pretreated and treated group throughout reperfusion.. The findings from this study indicate that RVT has potent cardioprotective properties against I/R injury in rat hearts. The study also highlighted that the administration of RVT, as pretreatment, has amplified the beneficial effects over the standard treatment.

Topics: Analysis of Variance; Animals; Coronary Circulation; Disease Models, Animal; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Sensitivity and Specificity; Stilbenes; Survival Rate

We used two experimental models to prove that resveratrol (trans-3,4',5-trihydroxystilbene) reduces cardiac ischemic-reperfusion injury by means of a nitric oxide- and adenosine-dependent mechanism. (1). ACUTE EX VIVO: resveratrol (10 microM, 10 min) infusion in Langendorff-perfused normoxic rat hearts significantly increased adenosine release and coronary flow compared with baseline. After 30-min low-flow ischemia, vasodilation, still present at reperfusion, was completely abolished by resveratrol plus adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT, 50 microM) administration. (2). CHRONIC IN VIVO: rats received tap water containing 25 mg/l resveratrol for 15 days or normal water. Twenty-four hours after, their hearts were Langendorff-perfused and submitted to 60-min low-flow ischemia and reperfusion. The resveratrol-treated hearts showed better functional recovery at reperfusion and significant vasodilation, but no variation in high-energy phosphates (31P Nuclear Magnetic Resonance). N(G)-nitro-L-arginine methyl ester (L-NAME, 30 microM), a nonselective nitric oxide synthase inhibitor, or SPT (50 microM) administered for 10 min prior to the low-flow ischemia cancelled the effects. This suggests that long-term moderate resveratrol consumption could play an important role in late cardioprotective effects.

Topics: Adenosine; Animals; Cardiotonic Agents; Coronary Circulation; Enzyme Inhibitors; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Theophylline; Time Factors; Vasodilator Agents

1. Dietary antioxidants are thought to be beneficial in reducing the incidence of coronary heart disease. In this study, we compared resveratrol and analogues on their antioxidation and free radical scavenging activities to their protective effects on ischaemia-reperfusion induced injuries of rat hearts. 2. Astringinin (3,3',4',5-tetrahydroxystilbene) was shown to be a more potent inhibitor than other analogues against Cu(2+)-induced LDL (low-density lipoprotein) oxidation, as measured by the formation of conjugated diene and TBARS (thiobarbituric acid-reactive substance) and by the electrophoretic mobility of the oxidized LDL. 3. Resveratrol (trans-3,4',5-trihydroxystilbene) and astringinin scavenged the stable free radical DPPH (1,1-diphenyl-2-picryl-hydrazyl) with an IC(0.200) of 7.1 and 4.3 microM, respectively. 4. Astringinin has a superoxide anion scavenging activity about 160 fold more potent than resveratrol. 5. After a 30 min global ischemia followed by 2 h reperfusion, astringinin (10 microM) significantly reduced infarct size, superoxide anion production and increased functional recovery of the coronary flow in Langendorff-perfused rat hearts. 6. The result showed there is a positive correlation between the anti-oxidation and cardioprotective activities among these phenolic compounds. Our finding together with the fact that astringinin is more water-soluble than resveratrol suggest that astringinin could potentially be used as an anti-oxidant and cardioprotective agent in biological systems.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Free Radical Scavengers; Humans; Lipoproteins, LDL; Male; Myocardial Ischemia; Oxidation-Reduction; Picrates; Protective Agents; Rats; Rats, Inbred WKY; Reperfusion Injury; Resveratrol; Stilbenes; Superoxides

Resveratrol (trans-3,4',5-trihydroxystilbene), a recently described grape-derived polyphenolic antioxidant, has been found to protect the heart from ischemic-reperfusion injury. The present study sought to determine the mechanism of cardioprotection by investigating the ability of resveratrol to precondition the heart. Isolated perfused rat hearts were randomly divided into six groups: group I was perfused for 15 min with Kreb-Henseleit buffer (KHB) only; group II was perfused with 10 microM resveratrol; group III was perfused with 10 microM resveratrol plus 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide (NO) synthase (NOS) inhibitor; group IV was perfused with 10 microM resveratrol plus 100 microM aminoguanidine (AG), an inducible NOS (iNOS) blocker; and groups V and VI consisted of hearts perfused with L-NAME and AG, respectively. The perfusion was then switched to working mode, and all hearts were made globally ischemic for 30 min followed by 2 h of reperfusion. Preconditioning of the hearts with resveratrol provided cardioprotection as evidenced by improved postischemic ventricular functional recovery (developed pressure and aortic flow) and reduced myocardial infarct size and cardiomyocyte apoptosis. Resveratrol-mediated cardioprotection was completely abolished by both L-NAME and AG. In a separate study, hearts were examined for iNOS mRNA induction. Resveratrol caused an induction of the expression of iNOS mRNA beginning at 30 min after reperfusion, increasing steadily up to 60 min of reperfusion, and then decreasing progressively up to 2 h after reperfusion. Preperfusion of the hearts with AG almost completely blocked the induction of iNOS. The results of our study demonstrate that resveratrol can pharmacologically precondition the heart in a NO-dependent manner.

Topics: Animals; Apoptosis; Enzyme Inhibitors; Gene Expression; Guanidines; Heart Ventricles; Ischemic Preconditioning; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Stilbenes

Protykin is an all-natural, high potency standardized extract of trans-resveratrol (20%) and emodin (10%) derived from the dried rhizome of Polygonum cuspidatum. Previous studies have demonstrated free radical scavenging and anti-inflammatory activities of resveratrol. Since free radicals play a crucial role in the pathogenesis of myocardial ischemia/reperfusion injury, we examined whether Protykin could preserve the heart during ischemic arrest. Sprague-Dawley rats were divided into two groups: experimental group was gavaged Protykin (100 mg/kg body wt) dissolved in corn oil for three weeks, while the control group was gavaged corn oil alone. After three weeks, rats were sacrificed, isolated hearts perfused via working mode, were made globally ischemic for 30 min followed by 2 h of reperfusion. Left ventricular functions were continuously monitored and malonaldehyde (MDA) (presumptive marker for oxidative stress) formation were estimated. At the end of each experiment, myocardial infarct size was measured by TTC staining method. Peroxyl radical scavenging activity of Protykin was determined by examining its ability to remove peroxyl radical generated by 2,2'-azobis (2-amidinopropane) dihydrochloride, while hydroxy radical scavenging activity was tested with its ability to reduce 7-OH*-coumarin-3-carboxylic acid. The results of our study demonstrated that the Protykin group provided cardioprotection as evidenced by improved post-ischemic left ventricular functions (dp, dp/dt(max)) and aortic flow as compared to control group. This was further supported by the reduced infarct size in the Protykin group. Formation of MDA was also reduced by Protykin treatment. In vitro studies demonstrated that Protykin possessed potent peroxyl and hydroxyl radical scavenging activities. The results of this study indicate that Protykin can provide cardioprotection, presumably by virtue of its potent free radical scavenging activity.

Topics: Animals; Antioxidants; Blood Pressure; Coronary Vessels; Emodin; Fluoresceins; Free Radical Scavengers; Gamma Rays; Hydroxyl Radical; Male; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Peroxides; Polygonaceae; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Resveratrol is a grape component with complex pharmacology related to its antioxidant activity. Little is known about the direct effects of resveratrol on the myocardium. We tested whether resveratrol administration before ischemia could attenuate ischemic/reperfusion damage. We examined how resveratrol affects high-energy phosphate metabolism (31P-nuclear magnetic resonance) and contractility of isolated Langendorff perfused rat hearts subjected to 20 min no-flow ischemia and 30 min reperfusion. During 10 min resveratrol infusion (10 microM) before ischemia, basal phosphorylation potential dropped by 40% (p < 0.05 vs. preinfusion value) without affecting contractility. The level of effluent adenosine was increased by 68%, parallel to a 50% increase in coronary flow. Resveratrol significantly improved postischemic recovery of rate-pressure product (62 +/- 5.2 vs. 23 +/- 8.1% of controls; p < 0.05). The metabolic pattern following resveratrol infusion was similar to that produced by ischemic preconditioning, suggesting that an increase in adenosine availability is involved in cardioprotection.

Topics: Adenosine; Animals; Antioxidants; Cardiovascular Physiological Phenomena; Heart; Ischemic Preconditioning, Myocardial; Male; Muscle Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Phosphates; Phosphorylation; Rats; Rats, Sprague-Dawley; Recovery of Function; Regional Blood Flow; Reperfusion Injury; Resveratrol; Stilbenes

The major objective of the present study was to examine the cardioprotective effect of resveratrol, an antioxidant presents in red wines, in the rat after ischemia and ischemia-reperfusion (I-R).. The left main coronary artery was occluded for 30 or 5 min followed by a 30-min reperfusion in anesthetized rats. Animals were preinfused with and without resveratrol before occlusion and the severity of ischemia- and I-R-induced arrhythmias and mortality were compared.. Resveratrol pretreatment had no effect on ischemia-induced arrhythmias nor on mortality. In contrast, a dramatic protective effects were observed against I-R-induced arrhythmias and mortality. Resveratrol pretreatment both reduced the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF). During the same period, resveratrol pretreatment also increased nitric oxide (NO) and decreased lactate dehydrogenase levels in the carotid blood.. Resveratrol is a potent antiarrhythmic agent with cardioprotective properties in I-R rats. The cardioprotective effects of resveratrol in the I-R rats may be correlated with its antioxidant activity and upregulation of NO production.

Topics: Analysis of Variance; Animals; Antioxidants; Blood Pressure; Chi-Square Distribution; Free Radical Scavengers; Heart Rate; L-Lactate Dehydrogenase; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Rats; Rats, Sprague-Dawley; Resveratrol; Statistics, Nonparametric; Stilbenes; Tachycardia, Ventricular; Ventricular Fibrillation

The consumption of red wine has been reported to impart a greater benefit in the prevention of coronary heart disease than the consumption of other alcoholic beverages. This beneficial effect is increasingly being attributed to certain antioxidants comprising the polyphenol fraction of red wine such as transresveratrol. In the present study, we investigated the potential cardioprotective effects of resveratrol in the face of ischemia reperfusion (I/R) injury. Isolated perfused working rat hearts after stabilization were perfused with Krebs-Henseleit Bicarbonate buffer (KHB) either in the presence or absence of transresveratrol (RVT) at a concentration of 10 microM for 15 min prior to subjecting them to 30 min of global ischemia followed by 2 h of reperfusion. Left ventricular functions were monitored at various timepoints throughout the reperfusion period to assess the extent of postischemic recovery in comparison with baseline values. Coronary perfusate samples were also collected to determine malonaldehyde (MDA) levels. The results demonstrated that RVT exhibited significant myocardial protection. This was evidenced by improved recovery of post-ischemic ventricular function including developed pressure and aortic flow as compared to the control group (KHB). Values for developed pressure in the RVT-treated group were significantly higher than those in the control group throughout the reperfusion period (71.09+/-4.88 mm Hg vs. 58.47+/-3.88 mm Hg, 68.87+/-5.07 mm Hg vs. 49.74+/-2.65 mm Hg and 51.67+/-3.95 mm Hg vs. 30.50+/-4.80 mm Hg at reperfusion timepoints R-15, R-60, and R-120, respectively). From R-30 onwards, aortic flow was markedly higher in the RVT treated group as compared with the control group, the differences being most significant at R-90 (32.45+/-2.19 ml/min vs. 19.83+/-1.62 ml/min) and R-120 (27.15+/-2.27 ml/min vs. 14.10+/-1.69 ml/min). In contrast to the KHB treated group, the RVT-treated group displayed significant reduction in MDA formation especially in the immediate early reperfusion period (63.71+/-8.19 pM/ml vs. 130.86+/-4.76 pM/ml, 63.84+/-15.62 pM/ml vs. 156.99+/-18.93 pM/ml, 71.29+/-2.80 pM/ml vs. 129.5+/-10.30 pM/ml and 56.25+/-5.79 pM/ml vs. 127.99+/-3.50 pM/ml at timepoints R-1, R-3, R-5, and R-7, respectively) indicating a reduction in I/R injury related oxidative stress. Infarct size was markedly reduced in the RVT group when compared with the control group (10.57+/-0.35% vs. 36.27+/-5.28%). In vitro studies revealed RVT to

Topics: Animals; Antioxidants; Free Radicals; Heart; In Vitro Techniques; Male; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Peroxides; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Wine