Influence of Gender on Intrinsic Contractile Properties of Isolated Ventricular Myocytes from Calmodulin‐Induced Diabetic Transgenic Mice

Abstract

Diabetes mellitus impairs ventricular function, which itself may be disparately influenced by gender. This study compared the impact of gender on cardiac contractile response in ventricular myocytes from wild-type FVB and calmodulin-induced diabetic transgenic (OVE26) mice at young (2 month) and older (11 month) age. Mechanical and intracellular Ca 2þ properties of cardiac myocytes were evaluated using an IonOptix MyoCam 1 system. Diabetic mice of both genders exhibited significantly elevated blood glucose regardless of age. OVE26 myocytes displayed reduced peak shortening (PS) and maximal velocity of shortening=relengthening (AEdL=dt), and prolonged time-to-PS (TPS) and time-to-90% relengthening (TR 90 ), associated with higher resting intracellular Ca 2þ levels and attenuated Ca 2þ -induced intracellular Ca 2þ release compared with the FVB myocytes. Peak shortening and AEdL=dt were smaller in female FVB groups when compared to the age-matched male counterparts. However, these gender differences were ablated by the diabetic state. No significant gender-related differences in intracellular Ca 2þ handling were noted in either FVB or OVE26 myocytes, with the exception of overt gender differences in OVE26 mice when age was taken into account. Young female OVE26 mice exhibited better-preserved mechanical function while older female OVE26 mice displayed the worst mechanical function among all four OVE26 groups. In conclusion, our data confirmed impaired cardiac contractile function in diabetes, partially due to altered intracellular Ca 2þ handling, in both genders. Mechanical differences existed between genders but were ''cancelled off'' by diabetic state. Nevertheless, a ''female advantage'' in ventricular function may still persist in young female diabetic subjects.

Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus

“…These alterations are characteristic of diabetic cardiomyopathy and are consistent with our earlier findings using both genetically predisposed and chemically induced diabetic models (7,22,24,29,41,42 (7, 23, 29 -31, 40). Both mechanical and intracellular Ca 2ϩ defects triggered by diabetes were alleviated by metallothionein in both sexes, in a manner similar to its effect found in the genetically predisposed diabetes (41) and diet-induced prediabetic insulin resistance (8).…”

“…myocardial and cardiomyocyte contractile function have long been established, mainly manifested as differences in myocardial contractility, duration, and velocity of contraction and relaxation as well as stress tolerance to ischemia-reperfusion injury (1,5,23,42). Although differences in ovarian sex hormones, especially the potent antioxidant capacity associated with estrogen, have been speculated to play a major role in this "sex bias" of myocardial contractile function (1,23,26), the precise mechanism of action behind sex differences in intrinsic (i.e., basal physiological) cardiac function and diabetic cardiomyopathy still remains unclear.…”

A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age

“…It was of interest that there was a significant interaction of diabetes and sex among HF patients ⩾65 years, but not among younger patients. Studies in rat models of diabetes demonstrate that pro-survival signalling pathways and cardiac contractile function were preserved in young females but depressed in age-matched males with streptozotocin-induced diabetes 28 29. However, the protective effects of female gender were negated by advanced age in rodent models of diabetes 30.…”

Rodent models of diabetic cardiomyopathy

“…shortening, prolonged time to 90% re-lengthening, and reduced maximal velocities of shortening and re-lengthening Ye et al, 2003;Zhang et al, 2003). By contrast, no significant reduction of contractile force was observed in Langendorff perfusions of OVE26 diabetic hearts (Liang et al, 2002).…”