fr-167653 and Heart-Failure

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.. 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.. 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.

Topics: Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Heart Failure; Heart Ventricles; Imidazoles; Immunohistochemistry; In Situ Nick-End Labeling; Intracellular Membranes; Membrane Potentials; Mitochondria; Mitogen-Activated Protein Kinases; Norepinephrine; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Rats; Rats, Inbred Dahl; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Signal Transduction; Transfection