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Nitric oxide (NO) produced by endothelial NO synthase (eNOS) exerts beneficial effects in a variety of cardiovascular disease states. Studies on the benefit of eNOS activity in pressure-overload cardiac hypertrophy and dysfunction produced by aortic stenosis are equivocal, which may be due to different expression levels of eNOS or different severities of pressure-overload. Consequently, we investigated the effects of eNOS-expression level on cardiac hypertrophy and dysfunction produced by mild or severe pressure-overload. To unravel the impact of eNOS on pressure-overload cardiac dysfunction we subjected eNOS deficient, wildtype and eNOS overexpressing transgenic (eNOS-Tg) mice to 8 weeks of mild or severe transverse aortic constriction (TAC) and studied cardiac geometry and function at the whole organ and tissue level. In both mild and severe TAC, lack of eNOS ameliorated, whereas eNOS overexpression aggravated, TAC-induced cardiac remodeling and dysfunction. Moreover, the detrimental effects of eNOS in severe TAC were associated with aggravation of TAC-induced NOS-dependent oxidative stress and by further elevation of eNOS monomer levels, consistent with enhanced eNOS uncoupling. In the presence of TAC, scavenging of reactive oxygen species with N-acetylcysteine reduced eNOS S-glutathionylation, eNOS monomer and NOS-dependent superoxide levels in eNOS-Tg mice to wildtype levels. Accordingly, N-acetylcysteine improved cardiac function in eNOS-Tg but not in wildtype mice with TAC. In conclusion, independent of the severity of TAC, eNOS aggravates cardiac remodeling and dysfunction, which appears due to TAC-induced eNOS uncoupling and superoxide production. [ABSTRACT FROM AUTHOR]

Abstract: Exercise training attenuates left ventricular (LV) dysfunction after myocardial infarction (MI). It could be speculated that these effects of exercise are mediated by increased endothelial NO synthase (eNOS) activity. In the present study we tested the hypothesis that eNOS plays a critical role in the exercise-induced amelioration of LV dysfunction after MI. MI or sham was induced in eNOS−/−, eNOS+/− and eNOS+/+ mice. After 8weeks of voluntary wheel running (∼7km/day in all groups) or sedentary housing, global cardiac function was determined in vivo and (immuno)histochemistry was performed to assess cardiomyocyte size, fibrosis, capillary density and apoptosis in remote myocardium. At baseline eNOS−/− mice had higher mean aortic pressure compared to eNOS+/− and eNOS+/+ mice, but had normal global cardiac function. MI resulted in marked LV remodeling, including cardiomyocyte hypertrophy and a reduction in capillary density, increased fibrosis and apoptosis, as well as LV systolic and diastolic dysfunction to the same extent in all genotypes. In eNOS+/+ MI mice exercise abolished fibrosis and apoptosis in the remote myocardium, attenuated LV systolic dysfunction and ameliorated pulmonary congestion. These beneficial effects were lost in eNOS+/− and eNOS−/− mice, while LV systolic dysfunction and pulmonary congestion in eNOS+/− mice were exacerbated by exercise. In conclusion, the beneficial effects of exercise after MI on LV remodeling and dysfunction depend critically on endogenous eNOS. The observation that the lack of one eNOS allele is sufficient to negate all beneficial effects of exercise, strongly suggests that exercise depends on full eNOS expression. [Copyright &y& Elsevier]