Submitted on November 10, 2006
Accepted on March 30, 2007
Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload
Emmanuel Buys1, Michael J. Raher2, Sarah L. Blake3, Tomas G Neilan4, Amanda R Graveline1, Jonathan Passeri5, Miguel Llano5, Teresa M. Perez-Sanz5, Fumito Ichinose3, Stefan Janssens6, Warren M Zapol7, Michael H Picard5, Kenneth D. Bloch8, and Marielle Scherrer-Crosbie4*
1 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States
2 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
3 Cardiovascular Research Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
4 Cardiovascular Research Center, Cardiac Ultrasound Laboratory in the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
5 Cardiac Ultrasound Laboratory in the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
6 Cardiology Division and Center for Transgene Technology and Gene Therapy, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
7 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
8 Cardiovascular Research Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: marielle{at}crosbie.com.
Although nitric oxide synthase 3 (NOS3) is implicated as an important modulator of left ventricular (LV) remodeling, its role in the cardiac response to chronic pressure overload is controversial. We examined whether or not selective restoration of NOS3 to the hearts of NOS3-deficient mice would modulate the LV remodeling response to transverse aortic constriction (TAC).
LV structure and function were compared at baseline and after TAC in NOS3-deficient mice (NOS3-/-) and NOS3-/- mice carrying a transgene directing NOS3 expression specifically in cardiomyocytes (NOS3-/-TG). At baseline, echocardiographic assessment of LV dimensions and function, invasive hemodynamic measurements, LV mass and myocyte width did not differ between the two genotypes. Four weeks after TAC, echocardiographic and hemodynamic indices of LV systolic function indicated that contractile performance was better preserved in NOS3-/-TG mice than in NOS3-/- mice. Echocardiographic LV wall thickness and cardiomyocyte width were greater in the NOS3-/- mice athan in NOS3-/-TG mice. TAC-induced cardiac fibrosis did not differ between these genotypes. TAC increased cardiac superoxide generation in NOS3-/-TG but not in NOS3-/- mice. The ratio of NOS3 dimers to monomers did not differ before and after TAC in NOS3-/-TG mice.
Restoration of NOS3 to the heart of NOS3-deficient mice attenuates LV hypertrophy and dysfunction after TAC, suggesting that NOS3 protects against the adverse LV remodeling induced by prolonged pressure overload.
