Counterbalancing Effect of Estrogen on Nitric Oxide Dependent Mechanisms: Interactions with the Renin Angiotensin System

Jessup, Jewell. Wake Forest University School of Medicine Physiology and Pharmacology, 1 Medical Center Boulevard, Winston-Salem, NC 27157, United States.

Research suggests a cardioprotective role of estrogen through mechanisms that are not fully understood. A rat model with cardiac renin overexpression allowed for the dissection of how estrogen blunts the effect of hypertension on cardiac remodeling. Transgenic (TGR) hypertensive rats expressing the Ren-2 gene show a sexual dimorphism in terms of blood pressure that is associated with cardiac remodeling, insulin-resistance, and increased oxidative stress. To minimize genetic variability, a congenic model was derived from TGR [mRen2]27 rats and these studies were done in 7 intact and 7 ovariectomized (OVX) hypertensive rats (141 ± 7 and 171 ± 5 mmHg, respectively). OVX aggravated hypertension in association with significant changes in cardiac mass, contractility, and relaxation as evaluated by echocardiography. Administration of the specific neuronal nitric oxide synthase (nNOS) inhibitor, L-VNIO (0.5 mg/kg/day, 28 days, i.p.), reversed the hypertensive response induced by OVX (151 ± 8 vs. 171 ± 5 mmHg, P < 0.05) and cardiac hypertrophy. In OVX rats, the increased perivascular fibrosis and soluble cardiac collagen decreased with nNOS inhibition. Further evidence of the estrogen and cardiac nitric oxide interaction in this renin-dependent hypertensive model is shown through increased cardiac nNOS protein expression and its suppression following nNOS inhibition. In contrast, neither OVX nor nNOS inhibition altered cardiac eNOS expression. Since studies demonstrated that 3-week aliskiren therapy reversed cardiac hypertrophy and remodeling associated with reduced cardiac immunostaining for 3-nitrotyrosine and NADPH oxidase subunits (p47 and Rac1) in the [mRen2]27, these data reveal a critical interaction among cardiac angiotensin II, estrogen, and increased nNOS due to oxidative stress. This interpretation is supported by a dramatic reduction in cardiac nitric oxide production in estrogen-deplete animals, which was reversed by nNOS inhibition.