Abstract 14813: eNOS induced Oxidative Stress exacerbates Pressure-Overload induced LV Hypertrophy and Dysfunction and masks Beneficial Effects of eNOS Overexpression
Although initiated as a compensatory mechanism, pressure-overload induced left ventricular hypertrophy (LVH) increases the risk for heart failure. Previously, we showed endothelial Nitric Oxide synthase (eNOS) to be protective against myocardial infarction induced LV dysfunction. However, the role of eNOS in pressure overload induced ventricular remodeling remains controversial. Consequently, we studied the effect of eNOS expression levels on LVH and LV function 8 weeks after transverse aortic constriction (TAC, n=48) in eNOS knockout (Ko), wildtype (Wt) and eNOS overexpressing transgenic (Tg) mice. eNOS expression levels affected aortic pressure (Ko: 100±4 mmHg, Wt: 87±4 mmHg, Tg: 72±4 mmHg) but did not influence LV weight and function in sham operated mice (n=41). TAC produced LVH and dilation, decreased LVdP/dtP40 and induced pulmonary congestion (lung fluid weight/tibia length) and interstitial fibrosis in Wt mice. Surprisingly, in spite of the beneficial effects of eNOS levels on afterload, the effects of TAC on LVH and LV function were less detrimental in eNOS-Ko and aggravated in eNOS-Tg mice (Table 1). Subsequently we investigated whether eNOS-uncoupling induced oxidative stress prevented protective effects of eNOS overexpression. TAC significantly increased uncoupling ratio three fold in eNOS-Tg mice. Moreover, scavenging of reactive oxygen species (ROS) with N-acetyl cysteine (NAC) had only mild effects in eNOS-Wt mice (P=0.08 for relative lung fluid weight and P>0.1 for all other parameters) but prevented LV dilation (3.7±0.1 mm), reduced relative LV weight (85±5 mg/cm) and lung fluid weight (91±11 mg/cm) and improved fractional shortening (26±4 %) in eNOS-Tg mice. In conclusion, eNOS does not reduce but rather elevates pressure-overload induced ROS, thereby masking beneficial effects of NO.
- Nitric oxide synthase
- Free radicals/Free-radical scavengers
- Ventricular remodeling
- Ventricular function
- Aortic stenosis
- © 2011 by American Heart Association, Inc.