title: Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse.
abstract: We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1α (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1α-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Second Department of Internal Medicine, School of Medicine, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Furuno
authors.affiliation: Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.affiliation: Third Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arakaki
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kina-Tanada
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Haruaki
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Sakanashi
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Nakasone
authors.affiliation: Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Department of Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ishiuchi
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.affiliation: Third Department of Internal Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohya
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.affiliation: Second Department of Internal Medicine, School of Medicine, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Otsuji
authors.affiliation: Second Department of Internal Medicine, School of Medicine, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. Electronic address: tsutsui@med.u-ryukyu.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D019001:Nitric Oxide Synthase
keywords: Acute myocardial infarction; Arteriosclerosis; Nitric oxide synthase; Sudden cardiac death