Cholesterol homeostasis in cultures of rat heart myocytes: relationship to cellular hypertrophy.
The mechanism leading to accumulation of cholesterol in hypertrophic cultures of neonatal rat heart myocytes was investigated in light of its relevance to aging-related hypertrophy of myocardial tissue. Lipoprotein 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 increase in cholesterol levels. 3H2O incorporation into cell monolayers and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in cell-free extracts demonstrated a substantial increase in cholesterogenesis during culture aging. Cholesteryl ester (CE) synthesis, cellular levels, and acyl-CoA:cholesterol O-acyltransferase (ACAT) activity decreased. The rate of CE hydrolysis did not change. Although cholesterol efflux from cells decreased 50%, its relative contribution to cholesterol accumulation was small. Our results indicate that accumulation of cholesterol in aging rat myocyte cultures is primarily due to changes in the endogenous metabolism of cholesterol and not due to a lipoprotein-mediated pathway. This implicates an impairment of the feedback regulation of HMG-CoA reductase and ACAT. These findings have important implications for understanding the molecular mechanisms underlying aging-related myocardial hypertrophy.
Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
H
H
Shmeeda
D
D
Petkova
Y
Y
Barenholz
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D006706:Homeostasis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011865:Radioisotope Dilution Technique; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D014316:Tritium; D014867:Water / Q000378:metabolism
D002788:Cholesterol Esters; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014867:Water; D014316:Tritium; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase