Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction.
BACKGROUND
Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor kappaB (NF-kappaB) and given that NF-kappaB mediates cytoprotective responses, we asked whether NF-kappaB activation conferred cytoprotective responses in acute myocardial ischemia/infarction.


RESULTS
We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IkappaBalpha protein (IkappaBalphaDeltaN) that prevents nuclear translocation of NF-kappaB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was approximately 50% greater (P<0.02) in the IkappaBalphaDeltaN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IkappaBalphaDeltaN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IkappaBalphaDeltaN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity.


CONCLUSIONS
Transgenic mice with a defect in activation of NF-kappaB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-kappaB are mediated, at least in part, by Bcl-2 or c-IAP1.
Misra
Arunima
A
Winters Center for Heart Failure Research, Medical Care Service Line, Houston Veterans Administration Medical Center, Houston, Tex 77030, USA.
Haudek
Sandra B
SB
Knuefermann
Pascal
P
Vallejo
Jesus G
JG
Chen
Zhijian J
ZJ
Michael
Lloyd H
LH
Sivasubramanian
Natarajan
N
Olson
Eric N
EN
Entman
Mark L
ML
Mann
Douglas L
DL
D000818:Animals; D017209:Apoptosis; D003331:Coronary Vessels / Q000601:surgery; D019610:Cytoprotection; D020672:I-kappa B Proteins / Q000235:genetics; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D017202:Myocardial Ischemia / Q000150:complications; D032383:Myocytes, Cardiac / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha