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(Circulation. 2009;120:1222-1230.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Gene Transfer of Inducible Nitric Oxide Synthase Affords Cardioprotection by Upregulating Heme Oxygenase-1 Via a Nuclear Factor-B-Dependent Pathway

Qianhong Li, MD, PhD; Yiru Guo, MD; Qinghui Ou, MD; Chuanjue Cui, MD; Wen-Jian Wu, MSc; Wei Tan, MD; Xiaoping Zhu, MD; Lilibeth B. Lanceta, BS; Santosh K. Sanganalmath, MD; Buddhadeb Dawn, MD; Ken Shinmura, MD, PhD; Gregg D. Rokosh, PhD; Shuyan Wang, MD; Roberto Bolli, MD

From the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (Q.L., Y.G., Q.O., C.C., W.J.W., W.T., X.Z., L.B.L., S.K.S., B.D., G.D.R., S.W., R.B.); Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan (K.S.).

Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu

Received December 22, 2008; accepted July 21, 2009.

Background— Although inducible nitric oxide synthase (iNOS) is known to impart powerful protection against myocardial infarction, the mechanism for this salubrious action remains unclear.

Methods and Results— Adenovirus-mediated iNOS gene transfer in mice resulted 48 to 72 hours later in increased expression not only of iNOS protein but also of heme oxygenase (HO)-1 mRNA and protein; HO-2 protein expression did not change. iNOS gene transfer markedly reduced infarct size in wild-type mice, but this effect was completely abrogated in HO-1^–/– mice. At 48 hours after iNOS gene transfer, nuclear factor-B was markedly activated. In transgenic mice with cardiomyocyte-restricted expression of a dominant negative mutant of IB (IB^S32A,S36A), both basal HO-1 levels and upregulation of HO-1 by iNOS gene transfer were suppressed. Chromatin immunoprecipitation analysis of mouse hearts provided direct evidence that nuclear factor-B subunits p50 and p65 were recruited to the HO-1 gene promoter (–468 to –459 bp) 48 hours after iNOS gene transfer.

Conclusions— This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOS and cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-B binding to the region of the HO-1 gene promoter from –468 to –459 bp, and HO-1 then mediates the cardioprotective effects of iNOS. These results also reveal an important role of nuclear factor-B in both basal and iNOS-induced expression of cardiac HO-1. Collectively, the present findings significantly expand our understanding of the regulation of cardiac HO-1 and of the mechanism whereby iNOS exerts its cardioprotective actions.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1165-1167. [Extract] [Full Text]