title: Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency.
abstract: To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling induced by chronic pressure overload, the impact of transverse aortic constriction (TAC) on LV structure and function was compared in wild-type (WT) and NOS3-deficient (NOS3(-/-)) mice. Before TAC, LV wall thickness, mass, and fractional shortening were similar in the two mouse strains. Twenty-eight days after TAC, both WT and NOS3(-/-) mice had increased LV wall thickness and mass as well as decreased fractional shortening. Although the pressure gradient across the TAC was similar in both strains of mice 28 days after TAC, LV mass and posterior wall thickness were greater in NOS3(-/-) than in WT mice, whereas fractional shortening and the maximum rate of developed LV pressure were less. Diastolic function, as measured by the time constant of isovolumic relaxation and the maximum rate of LV pressure decay, was impaired to a greater extent in NOS3(-/-) than in WT mice. The degree of myocyte hypertrophy and LV fibrosis was greater in NOS3(-/-) than in WT mice at 28 days after TAC. Mortality was greater in NOS3(-/-) than in WT mice 28 days after TAC. Long-term administration of hydralazine normalized the blood pressure and prevented the LV dilation in NOS3(-/-) mice but did not prevent the LV hypertrophy, dysfunction, and fibrosis associated with NOS3 deficiency after TAC. These results suggest that the absence of NOS3 augments LV dysfunction and remodeling in a murine model of chronic pressure overload.
authors.affiliation: Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA. ichinose@etherdome.mgh.harvard.edu
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Justina C
authors.initials: JC
authors.lastname: Wu
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hataishi
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Aretz
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*
chemical_list: D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse