Premature death and age-related cardiac dysfunction in male eNOS-knockout mice.
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 microl 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.
Li
Wei
W
Department of Physiology, New York Medical College, Valhalla, NY, USA.
Mital
Seema
S
Ojaimi
Caroline
C
Csiszar
Anna
A
Kaley
Gabor
G
Hintze
Thomas H
TH
D000375:Aging / Q000473:pathology* / Q000502:physiology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006973:Hypertension / Q000235:genetics / Q000473:pathology; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000235:genetics* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012737:Sex Factors; D013318:Stroke Volume / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse