Abstract 1614: Inducible Nitric Oxide Synthase Upregulates Heme Oxygenase-1 (HO-1) in Myocardium by Enhancing Nrf2 Phosphorylation and Binding to the HO-1 Promoter
| Autor: | Qianhong Li, Qinghui Ou, Wei Tan, Wen-Jian Wu, Xiaoping Zhu, Lilibeth B Lanceta, Gregg D Rokosh, Yiru Guo, Roberto Bolli |
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| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Circulation. 118 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.118.suppl_18.s_358 |
| Popis: | Previous studies have shown that iNOS gene transfer leads to elevated expression of HO-1, which in turn protects against ischemic injury. However, the mechanism of this effect is unknown. Recently, Nrf2 has emerged as a key transcription factor in response to stress. Thus, we hypothesized that the upregulation of HO-1 by iNOS gene therapy involves an Nrf2-mediated pathway. Mice received injections in anterior LV wall of Av3/LacZ or Av3/iNOS; 3 days later, they were subjected to a 30-min coronary occlusion and 4 h of reperfusion. At 24 h after iNOS gene transfer (confirmed by iNOS immunoblotting), phosphorylated Nrf2 increased significantly in the myocardial nuclear fraction (+ 220% vs. LacZ group, n=6, P ); chromatin Nrf2-immunoprecipitation (Nrf2-ChIP) analysis in vivo showed that Nrf2 was specifically recruited to the HO-1 gene promoter (+ 4.7-fold vs. LacZ group, n=4, P ). At 3 days after iNOS gene transfer, myocardial HO-1 protein expression increased markedly (+ 2.6-fold vs. LacZ group, n=6, P ), but HO-2 did not change (n=3). The infarct-sparing effects of iNOS gene therapy were completely abrogated by disruption of Nrf2 (Nrf2−/−) (62.8±2.1% in Nrf2−/−+Av3/iNOS group, n=5, vs. 15.3±4.3% in WT+Av3/iNOS group, n=7; Fig ). We conclude that iNOS upregulates HO-1 by enhancing Nrf2 phosphorylation and binding to the HO-1 promoter; and targeted disruption of the Nrf2 gene completely abrogates cardioprotection after iNOS gene transfer. These results provide unequivocal molecular genetic evidence for a necessary role of Nrf2 in the protection afforded by iNOS. Thus, activation of Nrf2 is a key molecular event that links iNOS to HO-1. |
| Databáze: | OpenAIRE |
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