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(Circulation Research. 2001;88:305.)
© 2001 American Heart Association, Inc.

Cellular Biology

Cytoprotection by Jun Kinase During Nitric Oxide–Induced Cardiac Myocyte Apoptosis

Peter Andreka, Jie Zang, Christopher Dougherty, Tatiana I. Slepak, Keith A. Webster, Nanette H. Bishopric

From the Department of Molecular and Cellular Pharmacology, University of Miami, Fla.

Correspondence to Nanette H. Bishopric, M.D., University of Miami School of Medicine, RMSB 6038, 1600 NW 10th Ave, Miami, FL 33136. E-mail nhb{at}chroma.med.miami.edu

Abstract—Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal–regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (50-fold) activation of JNK1/2. Activation of JNK was cGMP dependent and was inversely related to NO concentration; it was maximal at the lowest dose of GSNO (10 µmol/L) and negligible at 1 mmol/L. NO slightly increased ERK1/2 beginning at 2 hours but did not affect p38MAPK activity. Inhibitors of ERK and p38MAPK activation did not affect cell death rates. In contrast, expression of dominant-negative JNK1 or MKK4 mutants significantly increased NO-induced apoptosis at 5 hours (56.77% and 57.37%, respectively, versus control, 40.5%), whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis in a JNK-dependent manner. Adenovirus-mediated expression of dominant-negative JNK1 both eliminated the rapid activation of JNK by NO and accelerated NO-mediated apoptosis by 2 hours. These data indicate that NO activates JNK as part of a cytoprotective response, concurrent with initiation of apoptotic signaling. Early, transient activation of JNK serves both to delay and to reduce the total extent of apoptosis in cardiac myocytes.

Key Words: apoptosis • cytoprotection • Jun kinase • nitric oxide • cGMP

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