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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1828    most recent 01117.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Milano, G. Articles by Vassalli, G. Search for Related Content PubMed PubMed Citation Articles by Milano, G. Articles by Vassalli, G.

A peptide inhibitor of c-Jun NH₂-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo

Departments of ¹Cardiovascular Surgery, ²Cardiology, ³Medical Genetics, and ⁴Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and ⁵Department of Medicine, University of Milan, San Paolo Hospital, Milan, Italy

Submitted 12 October 2006 ; accepted in final form 10 November 2006

The c-Jun NH₂-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, D-JNKI-1. Here we report on the effects of D-JNKI-1 in myocardial I/R. D-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. D-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture (P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia (P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function (P < 0.01). D-JNKI-1 reduced mitochondrial cytochrome-c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. D-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, D-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by 50% (P < 0.01). In conclusion, D-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.

myocardium; mitogen-activated protein kinases; apoptosis

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