Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 35, Issue 6, Pages 637-644Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/S0022-2828(03)00079-8
Keywords
aging; gender; hemodynamics; hypertrophy; murine; nitric oxide synthase; survival
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Funding
- NHLBI NIH HHS [R01 HL-65455, K08 HL-03238] Funding Source: Medline
- NIDDK NIH HHS [DK02568] Funding Source: Medline
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Deficiency of either neuronal nitric oxide synthase (NOS1) or endothelial nitric oxide synthase (NOS3) leads to cardiac hypertrophy in mice. Loss of both produces concentric left ventricular (LV) remodeling, in which increased wall thickness is accompanied by reduced cavity size. In humans. this phenotype develops in elderly hypertensive patients and independently predicts mortality. Accordingly, we tested the hypothesis that NOS1/3(-/-) mice have reduced longevity compared to either NOS1(-/-) or NOS3(-/-). Survival data on colonies of NOS 1(-/-) (n = 295), NOS3(-/-) (n = 525), and NOS1/3(-/-) (n = 331) mice were collected for 2 years. NOS1(-/-) mice had increased mortality compared to NOS3-/- (relative risk, RR 2.5. P < 0.001), whereas NOS 1/3(-/-) fared significantly worse (RR 7.3, P < 0.001 vs. NOS3(-/-)). Importantly, gender did not affect survival in NOS1(-/-) or NOS3(-/-), but male NOS 1/3(-/-) mice had 2-fold increased mortality compared to females. NOS1/3(-/-) mice developed progressive myocyte hypertrophy and interstitial fibrosis with age. NOS 1/3(-/-) mice underwent in vivo hemodynamic analysis with a combined pressure-volume catheter to assess age-related cardiovascular changes. Compared with control, NOS1/3(-/-) demonstrated hypertension and hypercontractility at all ages, and developed passive diastolic dysfunction with increasing age. Thus, combined deficiency of NOS1 and NOS3 causes increased mortality, myocyte hypertrophy, and an age-associated increase in ventricular stiffness. These findings suggest that cardiac NO signals may play an essential role in successful cardiac aging. (C) 2003 Elsevier Science Ltd. All rights reserved.
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