Premature death and age-related cardiac dysfunction in male eNOS-knockout mice

Abstract

The aims of our study were to determine mortality, and age- and genotype-related cardiac phenotype in endothelial nitric oxide synthase (NOS) knockout (–/–) and wild-type (+/+) mice. Male and female (–/–) and male and female (+/+) conscious mice were studied at different ages by echocardiography and tail-cuff blood pressure (BP) measurement. Only 50% male (–/–) mice lived longer than 21 months whereas 89% (+/+) mice were still alive after 24 months ( P < 0.005). There was little mortality in female mice of either genotype. Both (–/–) and (+/+) male mice have normal cardiac dimensions and function at 5.5 months. However, (–/–) mice developed cardiac dilation and dysfunction at 21 months as evidenced by a significant increase ( P < 0.05) in left ventricular (LV) end-diastolic diameter from 2.69 ± 0.13 to 3.13 ± 0.09 mm, LV end-systolic diameter from 1.28 ± 0.11 to 1.86 ± 0.12 mm, LV end-diastolic cavity volume from 21 ± 2.8 to 31 ± 2.5 μl and LV mass from 19 ± 2.5 to 27 ± 1.9 mg/10 g and a significant decrease ( P < 0.05) in ejection fraction (from 65 ± 3.3% to 41 ± 4.6%), shortening fraction (from 53 ± 2.2% to 41 ± 3.4%), LV posterior wall thickening (from 27 ± 2% to 12 ± 4%) and septum thickening (from 27 ± 2% to 12 ± 4%) compared with those at 5.5 months. There was a clear increase in cardiac weight and cardiac dilation by hematoxylin and eosin in male (–/–) mice at 21 months. BP in male (–/–) mice fell with the cardiac dysfunction, whereas female (–/–) mice were hypertensive even at 21 months. The level of mRNA for neuronal NOS and inducible NOS was greater in all females compared to males. These results indicate that male (–/–) mice have a significantly shorter lifespan than (+/+) or female mice, and male (–/–) mice develop cardiac dysfunction with age.