Submitted on March 14, 2006
Accepted on November 10, 2006
Endothelial Nitric Oxide Synthase (NOS3) Knockout Decreases NOS2 Induction Limiting Hyperoxygenation and Conferring Protection in the Postischemic Heart
Xue Zhao1, Reong-Renn Chen2, Guanglong He2, Aiwen Zhang2, Arthur R. Strauch2, Lawrence Druhan3, and Jay L Zweier2*
1 Internal Medicine, The Ohio State University, Columbus, Ohio, United States; Cardiology, Second Military Medical University, Shanghai, ShangHai, China
2 Internal Medicine, The Ohio State University, Columbus, Ohio, United States
3 the Davis Heart and Lung Research Institute and the Division of Cardiovascular Medicine, The Ohio State University College of Medicine, Columbus, Ohio, United States
* To whom correspondence should be addressed. E-mail: jay.zweier{at}osumc.edu.
While we have shown that endothelial nitric oxide synthase (eNOS)-derived NO down regulates mitochondrial oxygen consumption during early reperfusion, its effects on inducible NOS (iNOS) induction and myocardial injury during late reperfusion is unknown. Wild-type (WT) and eNOS -/- mice were subjected to 30 min of coronary ligation followed by reperfusion. Expression of iNOS mRNA and protein levels, and peroxynitrite production were lower in postischemic myocardium of eNOS-/- mice than that in WT mice 48 hrs post reperfusion. Significantly improved hemodynamics (+-dp/dt, LVSP, MAP), increased rate pressure product and reduced myocardial infarct size (18 +- 2.5% vs 31+-4.6%) were found 48 hrs after reperfusion in eNOS-/- mice compared to WT mice. Myocardial infarct size was also significantly decreased in WT mice treated with 1400W (20.5 +- 3.4%) compared to WT mice treated with PBS (33.9 +- 5.3%). A marked reperfusion-induced hyperoxygenation state was observed by electron paramagnetic resonance oximetry in postischemic myocardium, but PO2 values were significantly lower from 1 hr to 72 hrs in eNOS-/- than in WT mice. Cytochrome c oxidase activity and NADH-dehydrogenase (NADH-DH) activity were significantly decreased in postischemic myocardium in WT and eNOS-/- mice compared to baseline control respectively, and NADH-DH activity was significantly higher in eNOS-/- mice than in WT. Thus, deficiency of eNOS exerted a sustained beneficial effect on postischemic myocardium 48 hrs after reperfusion with preserved mitochondrial function, which appears to be due to decreased iNOS induction and decreased iNOS-derived peroxynitrite in postischemic myocadium.
