title: Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction.
abstract: Nitric oxide (NO) is an important modulator of cardiac performance and left ventricular (LV) remodeling after myocardial infarction (MI). We tested the effect of cardiomyocyte-restricted overexpression of one NO synthase isoform, NOS3, on LV remodeling after MI in mice. LV structure and function before and after permanent LAD coronary artery ligation were compared in transgenic mice with cardiomyocyte-restricted NOS3 overexpression (NOS3-TG) and their wild-type littermates (WT). Before MI, systemic hemodynamic measurements, echocardiographic assessment of LV fractional shortening (FS), heart weight, and myocyte width (as assessed histologically) did not differ in NOS3-TG and WT mice. The inotropic response to graded doses of isoproterenol was significantly reduced in NOS3-TG mice. One week after LAD ligation, the infarcted fraction of the LV did not differ in WT and NOS3-TG mice (34+/-4% versus 36+/-12%, respectively). Four weeks after MI, however, end-systolic LVID was greater, and fractional shortening and maximum and minimum rates of LV pressure development were less in WT than in NOS3-TG mice. LV weight/body weight ratio was greater in WT than in NOS3-TG mice (5.3+/-0.2 versus 4.6+/-0.5 mg/g; P<0.01). Myocyte width in noninfarcted myocardium was greater in WT than in NOS3-TG mice (18.8+/-2.0 versus 16.6+/-1.6 microm; P<0.05), whereas fibrosis in noninfarcted myocardium was similar in both genotypes. Cardiomyocyte-restricted overexpression of NOS3 limits LV dysfunction and remodeling after MI, in part by decreasing myocyte hypertrophy in noninfarcted myocardium.
authors.affiliation: Cardiology Division and Center for Transgene Technology and Gene Therapy, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium. stefan.janssens@med.kuleuven.ac.be
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
authors.forename: Peter
authors.initials: P
authors.lastname: Pokreisz
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.forename: Marijke
authors.initials: M
authors.lastname: Pellens
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeersch
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Peter
authors.initials: P
authors.lastname: Jans
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szelid
authors.forename: Hilde
authors.initials: H
authors.lastname: Gillijns
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Desire
authors.initials: D
authors.lastname: Collen
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D004790:Enzyme Induction; D005355:Fibrosis; D006801:Humans; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000209:etiology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000502:physiology; D019076:Transgenes; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000502:physiology; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D011993:Recombinant Fusion Proteins; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D024723:Ventricular Myosins; D007545:Isoproterenol