17beta-estradiol regulates constitutive nitric oxide synthase expression differentially in the myocardium in response to pressure overload.
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.
Loyer
Xavier
X
Institut National de la Santé et de la Recherche Médicale, Unité 689, Centre de Recherche Cardiovasculaire INSERM Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France.
Damy
Thibaud
T
Chvojkova
Zuzana
Z
Robidel
Estelle
E
Marotte
Françoise
F
Oliviero
Patricia
P
Heymes
Christophe
C
Samuel
Jane-Lise
JL
D000818:Animals; D001013:Aorta, Thoracic; D051242:Caveolin 1 / Q000378:metabolism; D003250:Constriction; D004452:Echocardiography; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D047468:Immunoprecipitation; D009206:Myocardium / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar
D051242:Caveolin 1; D004958:Estradiol; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III