Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice.

Abstract

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 NOS1(-/-) (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 NOS1/3(-/-) fared significantly worse (RR 7.3, P < 0.001 vs. NOS3(-/-)). Importantly, gender did not affect survival in NOS1(-/-) or NOS3(-/-), but male NOS1/3(-/-) mice had 2-fold increased mortality compared to females. NOS1/3(-/-) mice developed progressive myocyte hypertrophy and interstitial fibrosis with age. NOS1/3(-/-) 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.

• Authors: Lili A Barouch, Thomas P Cappola, Robert W Harrison, Julie K Crone, E Rene Rodriguez, Arthur L Burnett, Joshua M Hare
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 35 Issue 6 Pg. 637-44 (Jun 2003) ISSN: 0022-2828 [Print] England
• PMID: 12788381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Protein Isoforms
• NOS1 protein, human
• NOS3 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos1 protein, mouse
• Nos3 protein, mouse

Topics

• Aging
• Animals
• Cardiomegaly (genetics)
• Female
• Gene Deletion
• Homozygote
• Humans
• Male
• Mice
• Mice, Transgenic
• Nitric Oxide Synthase (genetics, physiology)
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Phenotype
• Protein Isoforms
• Sex Factors
• Time Factors
• Ventricular Remodeling