Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse

Taro Uchida, Yumi Furuno, Akihide Tanimoto, Yumiko Toyohira, Kumiko Arakaki, Mika Kina-Tanada, Haruaki Kubota, Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Tomonori Igarashi, Susumu Ueno, Masayuki Matsushita, Shogo Ishiuchi, Hiroaki Masuzaki, Yusuke Ohya, Nobuyuki Yanagihara, Hiroaki Shimokawa, Yutaka OtsujiMasahito Tamura, Masato Tsutsui

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)29-41
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume77
DOIs
Publication statusPublished - 2014 Dec 1

Keywords

  • Acute myocardial infarction
  • Arteriosclerosis
  • Nitric oxide synthase
  • Sudden cardiac death

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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