doi: 10.1161/hc4901.100381
(Circulation. 2001;104:2948.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes
From the Department of Cardiovascular Medicine (E.I.-K., K.H., T.Y., Y.K., S.S.), Department of Pathology and Biology of Diseases (S.T.), and Department of Pediatrics (S.A.), Graduate School of Medicine, and College of Medical Technology (M.F.), Kyoto University, Kyoto, and National Cardiovascular Research Center, Osaka (T.S.), Japan.
Correspondence to Koji Hasegawa, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp
Background— Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1.
Methods and Results— In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2'-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK.
Conclusions— These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.
Key Words: lipoproteins • apoptosis • myocytes • heart failure • receptors
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