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Department of Physiology, New York Medical College, Valhalla, New York 10595
Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNF
, TNFß, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNF-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNF increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNF. Thus we propose that age-related upregulation of TNF and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.
TACE activity; caspase 9; small inhibitory RNA; senescence; cytokine; inflammation
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