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 NO 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 weeks after surgery for 11 weeks. Afterwards, cardiac function and degree of LV hypertrophy (LVH) were assessed by echocardiography. NOS activity and expression were studied by biochemical techniques.

TAC led to significant LVH (> 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+E2). Total NOS activity decreased significantly in Ovx groups. In response to TAC, total NOS activity increased whatever the E(2) status. Specific NOS3 activity dramatically decreased in Ovx groups (-55%, P<0.009) and was unaltered by TAC. By using co-immunoprecipitation 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.