Journal of Biological Chemistry
Volume 280, Issue 38, 23 September 2005, Pages 32602-32608
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Mechanisms of Signal Transduction
Genetic Inhibition or Activation of JNK1/2 Protects the Myocardium from Ischemia-Reperfusion-induced Cell Death in Vivo*

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The c-Jun NH2-terminal kinase (JNK) branch of the mitogen-activated protein kinase signaling cascade has been implicated in the regulation of apoptosis in a variety of mammalian cell types. In the heart, disagreement persists concerning the role that JNKs may play in regulating apoptosis, since both pro- and antiapoptotic regulatory functions have been reported in cultured cardiomyocytes. Here we report the first analysis of cardiomyocyte cell death due to JNK inhibition or activation in vivo using genetically modified mice. Three separate mouse models with selective JNK inhibition were assessed for ventricular damage and apoptosis levels following ischemia-reperfusion injury. jnk1–/–, jnk2–/–, and transgenic mice expressing dominant negative JNK1/2 within the heart were each shown to have less JNK activity in the heart and less injury and cellular apoptosis in vivo following ischemia-reperfusion injury. To potentially address the reciprocal gain-of-function phenotype associated with sustained JNK activation, transgenic mice were generated that express MKK7 in the heart. These transgenic mice displayed elevated cardiac c-Jun kinase activity but, ironically, were also significantly protected from ischemia-reperfusion. Mechanistically, JNK-inhibited mice showed increased phosphorylation of the proapoptotic factor Bad at position 112, whereas MKK7 transgenic mice showed decreased phosphorylation of this site. Collectively, these results underscore the complexity associated with JNK signaling in regulating apoptosis, such that sustained inhibition or activation both elicit cellular protection in vivo, although probably through different mechanisms.

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*

This work was supported by grants from the National Institutes of Health (NIH) (to J. D. M.), by an American Heart Association Established Investigator grant (to J. D. M), and by NIH National Research Service Award HL073550 (to R. A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Both authors contributed equally to this work.