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17ß-Estradiol Regulates Constitutive Nitric Oxide Synthase Expression Differentially in the Myocardium in Response to Pressure Overload

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 689 Centre de Recherche Cardiovasculaire INSERM Lariboisiére (X.L., T.D., Z.C., E.R., F.M., P.O., C.H., J.-L.S.), Institut Fèdèratif de Recherche 139, Université D. Diderot (X.L., T.D., Z.C., E.R., F.M., P.O., C.H., J.-L.S.), and Assistance Publique-Hôpitaux de Paris Hôpital Lariboisière (T.D.), Cedex 10, 75475 Paris, France

Address all correspondence and requests for reprints to: Dr. Jane-Lise Samuel, Institut National de la Santé et de la Recherche Médicale Unité 689 Centre de Recherche Cardiovasculaire INSERM Lariboisière, 41, Boulevard de la Chapelle, Cedex 10, 75475 Paris, France. E-mail: samuel{at}larib.inserm.fr.

Estrogens [E(2)] exert direct and indirect effects that can modulate the development of cardiac disease. However, the precise mechanisms that are involved remain undefined. Our objective was to investigate whether E(2) affected the activity and expression of constitutive nitric oxide synthase (NOS) isoforms (NOS3 and NOS1) in cardiac hypertrophy induced by thoracic aortic constriction (TAC). Ovariectomized (Ovx) and nonovariectomized Wistar rats were subjected to TAC. Ovx animals received E(2) or placebo 3 wk after surgery for 11 wk. Afterward cardiac function and degree of left ventricular hypertrophy were assessed by echocardiography. NOS activity and expression were studied by biochemical techniques. TAC led to significant left ventricular hypertrophy (>90%) irrespective of hormonal status. Cardiac performance declined more in TAC+Ovx (–20%, P < 0.015) than in the two other TAC groups [TAC and TAC+Ovx+E(2)]. Total NOS activity decreased significantly in the Ovx groups. In response to TAC, total NOS activity increased whatever the E(2) status. Specific NOS3 activity dramatically decreased in the Ovx groups (–55%, P < 0.009) and was unaltered by TAC. By using coimmunoprecipitation assays, we showed that NOS3/caveolin-1 complexes negatively regulated NOS3 activity as a function of E(2) status. On the other hand, NOS1 expression and activity were markedly increased in hypertrophied myocardium (P < 0.003), irrespective of E(2) status. This study demonstrates a differential regulation of NOS expression and activity in response to pressure overload and E(2) status, the former being mainly involved in the induction of NOS1, whereas the latter regulated NOS3 activity and in turn cardiac function.

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				X. Loyer, A. M. Gomez, P. Milliez, M. Fernandez-Velasco, P. Vangheluwe, L. Vinet, D. Charue, E. Vaudin, W. Zhang, Y. Sainte-Marie, et al. Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium Cycling Circulation, June 24, 2008; 117(25): 3187 - 3198. [Abstract] [Full Text] [PDF]

				X. Loyer, P. Oliviero, T. Damy, E. Robidel, F. Marotte, C. Heymes, and J.-L. Samuel Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2650 - H2658. [Abstract] [Full Text] [PDF]