Gender Differences in the beta-Adrenergic Signaling Mechanisms In Cardiac Hypertrophy and Heart Failure Due to Volume Overload

Our aim was to determine the nature and pattern of cardiac remodeling and contractile function in male and female rats in cardiac hypertrophy and congestive heart failure (CHF) in response to volume overload. Although gender differences for several etiologies of CHF are well documented, there is no in vivo study identifying male and female differences for hemodynamic and echocardiographic changes in hypertrophied and failing hearts due to volume overload. Both echocardiographic and hemodynamic alterations were determined in male and female Sprague-Dawley rats at 4 and 16 wks after the induction of AV shunt. In addition, ovariectomized female rats treated with or without estrogen for 16 wks post AV shunt were used. Both male and female rats developed cardiac hypertrophy at 4 wks post AV shunt, but an increase in cardiac output, internal diameters during diastole and systole as well as LVEDP; there was also a decrease in fractional shortening observed only in males. At 16 wks post AV shunt, cardiac hypertrophy was evident in both males and females; however, cardiac dysfunction marked by depressed +dP/dt, -dP/dt and increased LVEDP was observed in male rats only. Unlike female rats, male rats at 16 wks of AV shunt showed an increase in dLVID and sLVID associated with a depression in fractional shortening. Ovariectomized female rats exhibited changes similar to male animals upon inducing AV shunt for 16 wks; several of these alterations in hemodynamic and cardiac remodeling parameters were attenuated by 17-beta estradiol. In contrast to male rats which develop eccentric hypertrophy, concentric hypertrophy allows the female heart to accommodate the increased demand due to volume overload without impairment of cardiac function. Estrogen plays an important role in the prevention of cardiac dysfunction and remodeling in female rats subjected to volume overload.;We also sought to determine alterations In components of the beta-adrenergic signaling system in male and female rats at 4 and 16 wks after the induction of volume overload due to AV shunt. In addition, ovariectomized female rats treated with or without estrogen for 16 wks post AV shunt were used. Unlike in females at 4 wks after AV shunt a decrease in myocardial beta1 mRNA level was observed in male rats, whereas a specific increase in beta 2 mRNA level was seen only in female hearts. An increase in Gi mRNA was detected only in male rat heart at 4 wks after AV shunt. Furthermore, specific decreases in adenylyl cylase V/VI mRNA levels were observed only in male heart at 4 wks post AV shunt. Increases in beta-ARK1 gene expression were seen in both sexes, while only an increase in beta-ARK2 mRNA was seen in female rats at this time point. Although beta-arrestin1 mRNA was elevated only in the female, beta-arrestin2 gene expression was increased in both sexes at 4 wks post AV shunt. At 16 wks beta1-adrenoceptor mRNA levels were decreased in male rats, whereas increases in beta1 and beta2 adrenoceptor mRNA levels were seen in the female heart, with concomitant changes in beta1 and beta2 adrenoceptor protein contents. Specific decreases in adenylyl cyclase V/VI gene expression were only seen in males at this time point after the induction of volume overload. Furthermore, at this time point a specific increase in beta-ARK1 mRNA level was seen only in the female heart, whereas a specific decrease in beta-arrestin 2 gene expression was only detected in the male heart. Although, an increase in adenylyl cyclase was seen in 16 wk post AV shunt female rats, a decrease in adenylyl cyclase protein expression was detected in the ovariectomized female rat at 16 wks post AV shunt. Estrogen treatment resurrected the increase. While beta1 and beta2 protein contents were increased in the female heart, decreases were seen in the ovariectomized female rat. Estrogen treatment resulted in increases in beta1 and beta 2 protein expression.;In a second series of experiments we sought to determine whether there are gender differences in apoptotic signaling following induction of volume overload. It is well known that apoptosis contributes to the development of CHF and interestingly it was found that males have a significant amount of cardiomyocyte apoptosis 16 wks post-AV shunt with concurrent upregulation of pro-apoptotic factors such as phospho-Bad, Bax and caspase 3 and 9. Unlike females which demonstrate an increase in phospho-Bcl-2, males undergo a downregulation in anti-apoptotic phospho-Bcl-2 at 16 wks post AV shunt. The decrease in apoptosis and increase in phospho-Bcl-2 in female rats was abolished by ovariectomy; however with administration of estrogen apoptotic levels decreased to those similar to intact females.