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Administration of grape seed extract alleviates age-associated decline in ubiquitin-proteasome system and cardiomyocyte apoptosis in rats

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Author(s): Arun Kumar Vijayakumar | Vasanthan Kuppuswamy | Panneerselvam Chinnakkannu

Journal: Advances in Biological Chemistry
ISSN 2162-2183

Volume: 03;
Issue: 02;
Start page: 253;
Date: 2013;
Original page

Keywords: Aging | Proteasome Dysfunction | Cardiac Muscle Cell Death

ABSTRACT
Effective clearance of oxidized, damaged, and/or misfolded proteins in the cell by the ubiquitin-proteasome system (UPS) is critical for cell homeostasis, survival and function. We hypothesized that in the aging heart, generation of free radicals could impair UPS where the associated build-up of polyubiquitinated proteins could trigger programmed cell death. To test this, we used young (4 months old) and aged (24 months old) rats to analyze polyubiquitinated proteins, proteasome activity and programmed cell death in the ventricular tissue samples. Our studies reveal excessive deposition of polyubiquitinated proteins in the ventricular tissue extracts of old rats when compared to younger rats. The increased ubiquitination was accompanied by a significant decrease in 20S proteasome activity. Since the loss of proteasome-mediated clearance of ubiquitinated proteins is linked to programmed cell death, we measured TUNEL activity in aged rat heart and compared with younger animals. Aged animal hearts showed a substantial increase in programmed cell death as evidenced by TUNEL positive nuclei and DNA fragmentation. Analyses of cell death/survival pathways support our findings in terms of age-associated increase in the nuclear localization of p53, Bax/Bcl2 ratio and cleaved (active) caspase-3 and decreased expression of cellular inhibitor of apoptosis (cIAP1). Administration of grape seed extract (GSE) as a source of antioxidants significantly reduced these age-associated deleterious changes suggesting that free radicals primarily contribute to impaired UPS function and increased programmed cell death and that administration of antioxidants during aging could protect cardiac muscle cells and preserve ventricular function.
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