title: Inhibition of JNK aggravates the recovery of rat hearts after global ischemia: the role of mitochondrial JNK.
abstract: c-Jun N-terminal kinase (JNK), a stress-activated MAPK, is activated during cardiac ischemia-reperfusion (IR). The role of JNK inhibitors in cardioprotection against IR still remains controversial, in part, due to spill-over effects of non-specific inhibitors. In the present study, we sought to examine whether inhibition of JNK by SU3327, a specific JNK inhibitor that inhibits upstream JNK signaling rather than the kinase activity of JNK, improves cardiac function and reduces heart damage during IR. Hearts of male Sprague-Dawley rats perfused by Langendorff were subjected to 25 min of global ischemia followed by 30 min reperfusion in the presence or absence of SU3327. Cardiac function was monitored throughout the perfusion period. Myocardial damage was extrapolated from LDH activity in the coronary effluent. At the end of reperfusion, mitochondria were isolated and used to measure respiration rates and mitochondrial permeability transition pore opening. Protein analysis of mitochondria predictably revealed that SU3327 inhibited JNK phosphorylation. Although SU3327 significantly reduced cell damage during the first minutes of reperfusion, it did not improve cardiac function and, furthermore, reduced the mitochondrial respiratory control index. Interestingly, SU3327 activated the other stress-related MAPK, p38, and greatly increased its translocation to mitochondria. Mitochondrial P-JNK and P-p38 were co-immunoprecipitated with complex III of the electron transfer chain. Thus, JNK plays an essential role in cardiac signaling under both physiological and pathological conditions. Its inhibition by SU3327 during IR aggravates cardiac function. The detrimental effects of JNK inhibition are associated with reciprocal p38 activation and mitochondrial dysfunction.
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, United States of America.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, United States of America.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
mesh_terms: D000818:Animals; D002460:Cell Line; D006321:Heart / Q000503:physiopathology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047428:Protein Kinase Inhibitors; D048670:MAP Kinase Kinase 4