title: PKCbeta modulates ischemia-reperfusion injury in the heart.
abstract: Protein kinase C-betaII (PKCbetaII) is an important modulator of cellular stress responses. To test the hypothesis that PKCbetaII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCbeta-null (PKCbeta(-/-)) and wild-type mice fed the PKCbeta inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCbetaII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCbeta protected ischemic myocardium. Homozygous deletion of PKCbeta significantly diminished phosphorylation of c-Jun NH(2)-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCbeta in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCbeta may represent a potent strategy to protect the vulnerable myocardium.
authors.affiliation: Dept. of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Linghua
authors.initials: L
authors.lastname: Kong
authors.forename: Martin
authors.initials: M
authors.lastname: Andrassy
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Chang
authors.forename: Chun
authors.initials: C
authors.lastname: Huang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Szabolcs
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Yu Shan
authors.initials: YS
authors.lastname: Zou
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Shi Du
authors.initials: SD
authors.lastname: Yan
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Yan
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003331:Coronary Vessels / Q000601:surgery; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008026:Ligation; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C099154:ruboxistaurin; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048031:JNK Mitogen-Activated Protein Kinases; D003402:Creatine Kinase; C505409:Casp3 protein, mouse; D053148:Caspase 3