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(Circulation. 2003;108:3075-3078.)
© 2003 American Heart Association, Inc.

Brief Rapid Communication

Nuclear Factor-B Protects the Adult Cardiac Myocyte Against Ischemia-Induced Apoptosis in a Murine Model of Acute Myocardial Infarction

Arunima Misra, MD; Sandra B. Haudek, PhD; Pascal Knuefermann, MD; Jesus G. Vallejo, MD; Zhijian J. Chen, PhD; Lloyd H. Michael, PhD; Natarajan Sivasubramanian, PhD; Eric N. Olson, PhD; Mark L. Entman, MD; Douglas L. Mann, MD

From the Winters Center for Heart Failure Research, Medical Care Service Line, Houston Veterans Administration Medical Center; The DeBakey Heart Center and Cardiovascular Sciences (Z.J.C., E.N.O.), Methodist Hospital, Baylor College of Medicine, Houston; and Department of Molecular Biology (L.H.M., M.L.E.), University of Texas Southwestern Medical Center, Dallas, Tex.

Correspondence to Douglas L. Mann, MD, Winters Center for Heart Failure Research, 6565 Fannin, MS 524, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu

Received April 2, 2002; de novo received September 15, 2003; revision received October 27, 2003; accepted October 28, 2003.

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 B (NF-B) and given that NF-B mediates cytoprotective responses, we asked whether NF-B activation conferred cytoprotective responses in acute myocardial ischemia/infarction.

Methods and Results— We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IB protein (IBN) that prevents nuclear translocation of NF-B in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was 50% greater (P<0.02) in the IBN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IBN 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 IBN 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-B have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-B are mediated, at least in part, by Bcl-2 or c-IAP1.

Key Words: myocytes • apoptosis • myocardial infarction

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