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Am J Physiol Heart Circ Physiol (December 8, 2006). doi:10.1152/ajpheart.01117.2006
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Submitted on October 12, 2006
Accepted on November 10, 2006

A Peptide Inhibitor of c-Jun NH2-Terminal Kinase (JNK) Reduces Myocardial Ischemia/Reperfusion Injury and Infarct Size in Vivo

Giuseppina Milano, Sandrine Morel, Christophe Bonny, Michele Samaja1, Ludwig K von Segesser, Pascal Nicod2, and Giuseppe Vassalli3*

1 Department of Medicine, Surgery and Dentistry, University of Milan, Via di Rudini' 8, Milan, 20142, Italy
2 Medicine, CHUV, Switzerland
3 University Hospital Lausanne, Switzerland

* To whom correspondence should be addressed. E-mail: giuseppe.vassalli{at}chuv.ch.

Aims 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. Methods and results 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, occurred during I/R. D-JNKI-1 delivered before onset of ischemia prevented this 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 LV end-diastolic pressure during ischemia (p<0.01), and enhanced post-hypoxic 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-labelling (TUNEL; 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 prevented apoptosis. In vivo, D-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by ~50% (p<0.01). Conclusions D-JNKI-1 is an important compound that can be used in pre-clinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.




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