title: Nitric oxide synthases and heart failure - lessons from genetically manipulated mice.
abstract: Nitric oxide (NO) is synthesized by three distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human heart. The roles of NOSs in the pathogenesis of heart failure have been described in pharmacological studies with NOS inhibitors. Recently, genetically engineered animals have been used. We have generated mice in which all 3 NOS isoforms are completely disrupted (triple n/i/eNOS(-/-) mice). Morphological, echocardiographic, and hemodynamic analysis were performed in wild-type, singly nNOS(-/-), iNOS(-/-), eNOS(-/-), and triple n/i/eNOS(-/-) mice. Importantly, significant left ventricular (LV) hypertrophy and diastolic dysfunction was noted only in n/i/eNOS(-/-) mice, and those pathology was similar to diastolic heart failure in humans. Finally, treatment with an angiotensin II type 1 (AT1) receptor blocker, significantly prevented those abnormalities. These results provide the evidence that AT1 receptor pathway plays a center role in the pathogenesis of cardiac disorders in the n/i/eNOS(-/-) mice. Our studies with triple n/i/eNOS(-/-) mice provide pivotal insights into an understanding of the pathophysiology of NOSs in human heart failure.
authors.affiliation: Department of Second Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Shibata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Otsuji
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000201:enzymology*; D054144:Heart Failure, Diastolic / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology
chemical_list: D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III