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

Abstract

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 Ϫ/Ϫ 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 (Ϫ468 to Ϫ459 bp) 48 hours after iNOS gene transfer. Conclusions-This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOSand cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-B binding to the region of the HO-1 gene promoter from Ϫ468 to Ϫ459 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. (Circulation. 2009;120:1222-1230.)

Preconditioning c-Kit-positive Human Cardiac Stem Cells with a Nitric Oxide Donor Enhances Cell Survival through Activation of Survival Signaling Pathways

“…Interestingly, disruption of COX2 and HO-1 expression did not exhibit any attenuation of the cytoprotective effect, and knockdown of NRF2 only slightly impaired the NO-induced antiapoptotic role. There are additional in vivo studies confirming that COX2 and HO-1 play important roles in NO-mediated cardioprotection (57,58). Although these molecules are up-regulated by NO in hCSCs, our results suggest that NRF2, COX2, and HO-1 may not play dominant roles in NO-mediated antiapoptosis.…”

Hydrogen gas inhalation protects against liver ischemia/reperfusion injury by activating the NF-κB signaling pathway

“…NF-κB plays a critical role in mediating inflammatory and immune responses (13,14). Activation of NF-κB regulates an anti-apoptotic cascade and a number of anti-apoptotic genes including heme oxygenase, A20 and Bcl-2 (15,16). HO-1 is an inducible isoform produced in response to stress such as oxidative stress, hypoxia and cytokines (17).…”

Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential

“…Moreover, Li and colleagues have described a functional κB element in the mouse HO-1 promoter. These authors have shown that a mechanism involving the NF-κB subunits p50 and p65 as well as the inducible NO-synthase mediated HO-1 up-regulation in vivo [85].…”