Abstract 15251: Dual Role of Inducible Nitric Oxide Synthase in Left Ventricular Injury and Protection after Myocardial Infarction in Mice
Background: Uncoupling of nitric oxide synthase (NOS) plays a crucial role in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Although previous studies have indicated that endothelial NOS (eNOS) is a principal isoform of NOS generating nitric oxide (NO) and superoxide, we hypothesized that inducible NOS (iNOS) plays a central role in NO and superoxide generation, and LV protection and injury after MI.
Methods and Results: MI was created in wild-type (WT), neuronal NOS-knockout (nNOS−/−), iNOS-knockout (iNOS−/−), and endothelial NOS-knockout (eNOS−/−) mice by ligation of the left coronary artery. iNOS but not nNOS and eNOS expression was increased in endothelial cells (ETCs) after MI in WT mice associated with an increase in nitrotyrosine (NT) formation, a marker of superoxide/NO generation, and NOx, an index for bioavailability of NO within 48 hours after MI. LV diastolic and systolic dimensions and ejection fraction were not significantly different between all types of mouse hearts 4 weeks after MI. Tetrahydrobiopterin (BH4), a NOS co-factor, was significantly depleted in all types of mouse hearts subjected to MI. Oral administration of a precursor of BH4, sepiapterin (10 mg/kg/day), increased BH4 in WT mouse hearts and increased NOx and inhibited NT formation in ETCs. This inhibition of NOS uncoupling by sepiapterin was significantly blunted in iNOS−/− mice compared to WT, nNOS−/− and eNOS−/− mice. Administration of sepiapterin prevented ETC and cardiomyocyte apoptosis, increased angiogenesis and prevented LV remodeling and dysfunction after MI in WT, nNOS−/− and eNOS−/− mice but not in iNOS−/− mice. Combined administration of sepiapterin with an iNOS-selective inhibitor 1400W (10 mg/kg/day) abrogated the increase in NOx in WT, nNOS−/− and eNOS−/− mice but not in iNOS−/− mice. This was associated with the inhibition of the beneficial effects of sepiapterin on ETC and cardiomyocyte apoptosis, angiogenesis and LV remodeling and dysfunction.
Conclusions: These results suggest that iNOS plays a dual role in LV injury and protection after MI depending on its coupling status. Therefore, inhibition of iNOS uncoupling by sepiapterin may represent a promising approach to modulate LV remodeling and dysfunction after MI.
- © 2010 by American Heart Association, Inc.