Prevention of β-Adrenoceptor-Mediated Alterations in Female Heart Failure by Estrogen

Recent interest in Women Heart Health has led to increased attention to the influence and importance of sex in the incidence of cardiac dysfunction under a wide variety of stressful situations. It is now well known that pre-menopausal females are protected from several types of pathological stimuli leading to heart dysfunction. While the morbidity and mortality rates due to heart failure in pre-menopausal women are much less than their male counterparts, the mechanisms responsible are far from clear. Since the β-adrenergic system, which regulates heart function, is an integral pathway in the transition from cardiac hypertrophy to heart failure, this article is intended to present the evidence on sex differences in the β-adrenoceptor (β-AR) signaling mechanisms in a rat model of heart failure due to volume overload for 16 weeks. Both mRNA levels and protein content for β1-AR and β2-AR in female volume-overloaded hearts were elevated whereas these values were depressed in male failing hearts. Unlike female hearts, mRNA levels for adenylyl cyclase as well as β-arrestin 2 were depressed in male failing hearts whereas unlike male hearts, protein content for adenylyl cyclase and mRNA levels for GRK2 were increased in volume-overloaded female hearts. Ovariectomy for 16 weeks increased protein contents for β1-AR, β2-AR and adenylyl cyclase in control hearts whereas values for these components were depressed in the ovariectomized volume-overloaded hearts. These alterations due to ovariectomy were reversed by 17β-estradiol. Although ovariectomy depressed epinephrine-stimulated adenylyl cyclase activity in both control and volume-overloaded hearts, this change in control animals was not affected by 17β-estradiol. These observations support the view that estrogen plays an important role in augmenting β-AR-mediated signal transduction in female heart failure.