Abstract P636: Sex Differences in Cardioprotective AT2R Expression in Diabetic Rats and Its Correlation with Myocardial Damage

Abstract

Diabetes mellitus (DM) is an independent risk factor for cardiovascular disease (CVD). Healthy, young women are protected from CVD, while diabetic women are more susceptible to CVD compared to age-matched diabetic men and non-diabetic women. Underlying mechanisms for this sex difference in CVD are not fully elucidated. The angiotensin II type 2 receptor (AT2R) is a member of the protective, vasodilative arm of the renin angiotensin system. The Agtr2 gene that codes for AT2R is X-linked, and increased Agtr2 expression is reported in female vasculature of rodent models. We hypothesized that a sex difference might exist in DM-associated regulation of cardiac AT2R expression. To test this, we used hyperglycemic, male and female Zucker diabetic fatty (ZDF) rats and age- and sex-matched normoglycemic Zucker lean (ZL) rats. The male ZDF (ZDF-M) rat is an established model of type 2 DM. We have reported previously that hyperglycemic, female ZDF (ZDF-F) rats had the highest body fat and lowest lean muscle mass compared to male and female lean rats (ZL-M, ZL-F) and ZDF-M. Cardiac Agtr2 expression was measured by qRT-PCR at 5-months, cardiac function by echocardiography was compared at 3- and 5-months, and histopathology of cardiac tissue was assessed at 5-months. ZL-F had a nearly 2-fold increase of Agtr2 compared to ZL-M (p<0.01). Relative to lean controls, ZDF-M had no significant change in Agtr2, while ZDF-F exhibited ~60% suppression (Rq=0.42) of Agtr2 (p<0.001). Echocardiography data revealed evidence of compensated systolic function in all groups since fractional shortening was >50% at both ages, while heart rate and stroke volume were similar. However, diastolic dysfunction was observed in both ZDF-F and ZDF-M, relative to their lean counterparts, due to increased isovolumic relaxation time and decreased early:late ventricular filling ratio (E/A). ZDF-F exhibited the highest cardiomyocyte hypertrophy (≥35% over ZL-F, ZL-M and ZDF-M). Both ZDF and ZDF-M showed mitochondrial clustering and disrupted spatial orientation of mitochondria relative to the sarcomere (assessed by TEM). Based on our results, we propose that myocardial remodeling, diastolic dysfunction and loss of cardioprotective AT2R may underlie greater susceptibility of diabetic females to CVD.