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Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract
Debasis Bagchi1, Chandan K Sen, Sidhartha D Ray
1Department of Pharmacy Sciences, Medical Center, School of Pharmacy and Creighton University Health Professions, 2500 California Plaza, Omaha, NE 68178, USA. debsis@creighton.edu
Insights
Grape seed proanthocyanidin extract (GSPE) offers superior antioxidant and cardioprotective effects against cardiovascular diseases. GSPE reduces oxidative stress, improves heart function, and inhibits atherosclerosis and cardiotoxicity in various models.
Area of Science:
- Cardiovascular Medicine
- Oxidative Stress Research
- Nutraceutical Science
Background:
- Oxidative stress and free radicals are implicated in numerous cardiovascular diseases.
- Existing antioxidants like Vitamins C, E, and beta-carotene have limitations.
- Grape seed proanthocyanidin extract (GSPE) exhibits potent antioxidant properties.
Purpose of the Study:
- To evaluate the cardioprotective efficacy of GSPE.
- To investigate the mechanisms underlying GSPE's cardiovascular benefits.
- To assess GSPE's impact on oxidative stress markers and disease progression.
Main Methods:
- Animal studies using models of ischemic heart disease, doxorubicin-induced cardiotoxicity, and atherosclerosis.
- In vitro assessment of reactive oxygen species (ROS) and malondialdehyde (MDA) levels.
- Human clinical trial on hypercholesterolemic subjects.
- Gene expression analysis using cDNA microarray.
Main Results:
- GSPE improved cardiac function, reduced infarct size, and decreased arrhythmias in animal models.
- GSPE inhibited apoptosis and pro-apoptotic signaling pathways (JNK-1, c-JUN).
- GSPE reduced atherosclerosis biomarkers (foam cells) and oxidized LDL in humans, and inhibited endothelial CD36 expression.
Conclusions:
- GSPE demonstrates significant cardioprotective effects through potent antioxidant and anti-apoptotic mechanisms.
- GSPE shows promise in preventing and treating cardiovascular diseases, including atherosclerosis and drug-induced cardiotoxicity.
- GSPE may serve as a therapeutic agent for promoting cardiovascular health by modulating novel gene expression pathways.
Abstract:
Free radicals and oxidative stress play a crucial role in the pathophysiology of a broad spectrum of cardiovascular diseases including congestive heart failure, valvular heart disease, cardiomyopathy, hypertrophy, atherosclerosis and ischemic heart disease. We have demonstrated that IH636 grape seed proanthocyanidin extract (GSPE) provides superior antioxidant efficacy as compared to Vitamins C, E and beta-carotene. A series of studies were conducted using GSPE to demonstrate its cardioprotective ability in animals and humans. GSPE supplementation improved cardiac functional assessment including post-ischemic left ventricular function, reduced myocardial infarct size, reduced ventricular fibrillation (VF) and tachycardia, decreased the amount of reactive oxygen species (ROS) as detected by ESR spectroscopy and reduced malondialdehyde (MDA) formation in the heart perfusate. Cardiomyocyte apoptosis detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining. In concert, the proapoptotic signals mediated by JNK-l and c-fos proteins were also reduced suggesting that the novel cardioprotective properties of GSPE may be at least partially attributed to its ability to block anti-death signaling mediated through the proapoptotic transcription factors and genes such as JNK-1 and c-JUN. In a separate study, GSPE pretreatment significantly inhibited doxorubicin-induced cardiotoxicity as demonstrated by reduced serum creatine kinase (CK) activity, DNA damage and histopathological changes in the cardiac tissue of mice. Concentration-dependent efficacy of GSPE was also assessed in a hamster atherosclerosis model. Approximately 49 and 63% reduction in foam cells, a biomarker of early stage atherosclerosis, were observed following supplementation of 50 and 100 mg GSPE/kg body weight, respectively. A human clinical trial was conducted on hypercholesterolemic subjects. GSPE supplementation significantly reduced oxidized LDL, a biomarker of cardiovascular diseases. Finally, a cDNA microarray study demonstrated significant inhibition of inducible endothelial CD36 expression, a novel cardioregulatory gene, by GSPE. These results demonstrate that GSPE may serve as a potential therapeutic tool in promoting cardiovascular health via a number of novel mechanisms.