title: iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin.
abstract: Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS(-/-) and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS(-/-) mice had improved systolic performance (P < 0.001) and less heart block (P < 0.0001); larger sodium current density and lower serum TNF-alpha levels (P < 0.03); and less apoptosis (P < 0.01) resulting in improved survival (P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS(-/-) mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.
authors.affiliation: Libin Cardiovascular Institute, University of Calgary, HSC 1632, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Somers
authors.forename: Paul L
authors.initials: PL
authors.lastname: Beck
authors.forename: James P
authors.initials: JP
authors.lastname: Lees-Miller
authors.forename: Daniel
authors.initials: D
authors.lastname: Roach
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: Steven
authors.initials: S
authors.lastname: Loken
authors.forename: Shan
authors.initials: S
authors.lastname: Zhan
authors.forename: Lisa
authors.initials: L
authors.lastname: Semeniuk
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D019703:Calcineurin / Q000235:genetics* / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000502:physiology*; D003645:Death, Sudden; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006327:Heart Block / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019703:Calcineurin