CHOLESTEROL HOMEOSTASIS IN CULTURES OF RAT-HEART MYOCYTES - RELATIONSHIP TO CELLULAR HYPERTROPHY

The mechanism leading to accumulation of cholesterol in hypertrophic c ultures of neonatal rat heart myocytes was investigated in light of it s relevance to aging-related hypertrophy of myocardial tissue. Lipopro tein turnover was low in young cells (days 4-6) and further depressed in older cells (days 12-14), and therefore could not account for the i ncrease in cholesterol levels. (H2O)-H-3 incorporation into cell monol ayers and S-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in cell-free extracts demonstrated a substantial increase in cholester ogenesis during culture aging. Cholesteryl ester (CE) synthesis, cellu lar levels, and acyl-CoA:cholesterol O-acyltransferase (ACAT) activity decreased. The rate of CE hydrolysis did not change. Although cholest erol efflux from cells decreased 50%, its relative contribution to cho lesterol accumulation was small. Our results indicate that accumulatio n of cholesterol in aging rat myocyte cultures is primarily due to cha nges in the endogenous metabolism of cholesterol and not due to a lipo protein-mediated pathway. This implicates an impairment of the feedbac k regulation of HMG-CoA reductase and ACAT. These findings have import ant implications for understanding the molecular mechanisms underlying aging-related myocardial hypertrophy.