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Estrogen modulation of eNOS activity and its association with caveolin-3 and calmodulin in rat hearts
Xu Wang1, Abdel A Abdel-Rahman
1Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
Abstract:
Previous studies have shown that estrogen modulation of endothelial nitric oxide (NO) synthase (eNOS) may confer protection against heart disease. Here, we demonstrate an association between reductions in baroreflex-mediated bradycardia and in cardiac NOS activity in ovariectomized (Ovx) rats compared with controls. The latter resulted, at least in part, from a reduction in cardiac eNOS protein. eNOS-derived NO and its biological effects are determined by the levels of eNOS protein and by eNOS catalytic activity; the latter is regulated partly through the dynamic interaction with an inhibitory protein (caveolin) and a stimulatory protein (calmodulin). The association of eNOS immunoprecipitated with caveolin-3 and calmodulin was examined. Caveolin-3 and calmodulin binding with eNOS was increased and decreased, respectively, in Ovx rats. 17 beta-Estradiol replacement restored, to within normal levels, the baroreflex-mediated bradycardic responses along with eNOS activity, eNOS expression, and the association of eNOS with caveolin-3 and calmodulin. Our findings may help to elucidate the molecular mechanism underlying the favorable effects of estrogen on cardiac responses to baroreflex activation.
Insights
Estrogen replacement therapy in ovariectomized rats restored cardiac function and nitric oxide synthase (NOS) activity. This highlights estrogen
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Molecular Biology
Background:
- Estrogen's cardioprotective effects are partly mediated by endothelial nitric oxide synthase (eNOS).
- Ovariectomy (Ovx) in rats is associated with reduced baroreflex sensitivity and cardiac NOS activity.
- Cardiac eNOS protein levels and activity are crucial for nitric oxide (NO) production and function.
Purpose of the Study:
- To investigate the association between ovariectomy, cardiac NOS activity, and baroreflex function.
- To elucidate the molecular mechanisms involving eNOS, caveolin, and calmodulin in estrogen's cardiac effects.
- To determine the impact of 17 beta-estradiol replacement on these cardiac parameters.
Main Methods:
- Comparison of baroreflex-mediated bradycardia and cardiac NOS activity in ovariectomized (Ovx) rats versus control rats.
- Assessment of cardiac eNOS protein expression and its interaction with caveolin-3 and calmodulin.
- Evaluation of the effects of 17 beta-estradiol replacement therapy in Ovx rats.
Main Results:
- Ovariectomy reduced baroreflex-mediated bradycardia and cardiac NOS activity, linked to decreased cardiac eNOS protein.
- Ovariectomy increased binding of eNOS with inhibitory caveolin-3 and decreased binding with stimulatory calmodulin.
- 17 beta-estradiol replacement normalized baroreflex responses, eNOS activity, eNOS expression, and eNOS-protein interactions.
Conclusions:
- Estrogen plays a critical role in maintaining cardiac baroreflex function and eNOS activity.
- Estrogen modulates the interaction of eNOS with caveolin-3 and calmodulin, influencing NO bioavailability.
- These findings reveal a molecular mechanism for estrogen's beneficial effects on the heart's response to baroreflex activation.