PKCbeta modulates ischemia-reperfusion injury in the heart.
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.
Kong
Linghua
L
Dept. of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Andrassy
Martin
M
Chang
Jong Sun
JS
Huang
Chun
C
Asai
Tomohiro
T
Szabolcs
Matthias J
MJ
Homma
Shunichi
S
Liu
Rui
R
Zou
Yu Shan
YS
Leitges
Michael
M
Yan
Shi Du
SD
Ramasamy
Ravichandran
R
Schmidt
Ann Marie
AM
Yan
Shi-Fang
SF
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
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