Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes.

Abstract

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.

• Authors: E Iwai-Kanai, K Hasegawa, T Sawamura, M Fujita, T Yanazume, S Toyokuni, S Adachi, Y Kihara, S Sasayama
• Journal: Circulation (Circulation) Vol. 104 Issue 24 Pg. 2948-54 (Dec 11 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11739311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Enzyme Inhibitors
• FR 167653
• Imidazoles
• OLR1 protein, rat
• Pyrazoles
• Pyridines
• Receptors, LDL
• Receptors, Oxidized LDL
• Scavenger Receptors, Class E
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580
• Norepinephrine

Topics

• Animals
• Animals, Newborn
• Apoptosis (physiology)
• Cells, Cultured
• Endothelin-1 (pharmacology)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Heart Failure (metabolism)
• Heart Ventricles (cytology, drug effects, metabolism)
• Imidazoles (pharmacology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Intracellular Membranes (physiology)
• Membrane Potentials (physiology)
• Mitochondria (physiology)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Norepinephrine (pharmacology)
• Oxidative Stress (physiology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Inbred Dahl
• Receptors, LDL (biosynthesis, genetics, physiology)
• Receptors, Oxidized LDL
• Scavenger Receptors, Class E
• Signal Transduction (physiology)
• Transfection
• p38 Mitogen-Activated Protein Kinases