Abstract 629: Gender Differences In The Expression Of Cardioprotective Myeloid Cell Leukemia 1 (Mcl-1) In Diabetic Male And Female Rats

Diabetes Mellitus (DM) is an important risk factor for cardiovascular disease (CVD) and young, diabetic women are more susceptible to CVD compared to age-matched men and non-diabetic women. It is unclear how the progression of DM differentially affects cardiac pathology in males and females. In this context, recent studies have shown that myeloid cell leukemia 1 (MCL-1) plays an important role in cardiac protection and cardiac-specific ablation of Mcl-1 causes fatal dilated cardiomyopathy. We hypothesized that there is a gender difference in the expression of cardiac MCL-1 in young, diabetic males and females. To test this, we compared cardiac Mcl-1 expression in young rats (ages 11-12 weeks): diabetic males [ZDF obese (n=8)], non-diabetic females [ZDF lean (n=5)], and non-diabetic males [ZDF lean (n=8)] on Purina 5008 diet to young, diabetic female rats [ZDF obese (n=5)] on Research Diets D12468. Body composition analysis by EchoMRI showed that both male and female lean rats had increased muscle mass compared to their obese, diabetic counterparts, whereas obese, diabetic male and female rats had >5-fold increase in body fat than the corresponding lean controls (p<0.05). Fasting plasma insulin levels in lean female rats were lower than that seen in lean male rats; there was a 49-fold increase in diabetic females, and only a 12-fold increase in diabetic males, compared to lean counterparts (p<0.05). Fasting plasma glucose levels increased 2-3 fold in diabetic males and females, compared to lean controls (p<0.05). Quantitative RT-PCR analysis of mRNA isolated from cardiac tissues of lean and diabetic male and female rats showed that there was a 45% decrease in Mcl-1 mRNA in diabetic males compared to lean males, whereas there was an over 90% suppression of Mcl-1 mRNA in diabetic females compared to lean females (p<0.05). Previously, we have shown that insulin improves MCL-1 expression in female mouse cardiomyocytes. Data presented here suggest that although diabetic female rats have more severe hyperinsulinemia compared to diabetic male rats, loss of cardiac MCL-1 expression is more severe in diabetic females compared to diabetic males.This may underlie the loss of cardioprotective benefits in diabetic females.