Circulation Research. 2004
Published online before print March 25, 2004, doi: 10.1161/01.RES.0000126497.38281.23
Published online before print March 25, 2004, doi: 10.1161/01.RES.0000126497.38281.23
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Submitted on August 8, 2003
Revised on March 15, 2004
Accepted on March 15, 2004
Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction
Stefan Janssens *;
From the Center for Transgene Technology and Gene Therapy (S.J., P.P., M.P., P.V., M.T., P.J., Z.S., H.G., D.C.), Flanders Interuniversity Institute for Biotechnology, the Cardiology Division (S.J., F.V.d.W.), University Hospital Gasthuisberg, University of Leuven, and Thromb-X, LLC (L.S.), Belgium; and the Cardiology Division (M.S.-C., M.H.P., K.D.B.) and Cardiovascular Research Center (M.S.-C., K.D.B.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. E-mail: stefan.janssens{at}med.kuleuven.ac.be.
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 µm; 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.
Key words: nitric oxide synthase • myocardial infarction • left ventricular remodeling • myocyte hypertrophy
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