GENDER DISPARITY OF STREPTOZOTOCIN‐INDUCED INTRINSIC CONTRACTILE DYSFUNCTION IN MURINE VENTRICULAR MYOCYTES: ROLE OF CHRONIC ACTIVATION OF AKT

Abstract

1. Clinical, epidemiological and experimental evidence suggests a 'female advantage' in the progression of cardiovascular diseases, including diabetic cardiomyopathy. It is speculated that this 'gender bias' may be due to gender-related differences in sex hormones and intrinsic myocardial contractile properties. 2. The present study was designed to examine the impact of diabetes and gender on cardiac contractile function and activation of the cardiac survival signalling molecule Akt. Short-term (2 weeks) diabetes was induced in adult mice of both genders with streptozotocin (STZ). Mechanical and intracellular Ca(2+) properties of isolated ventricular myocytes were evaluated using an IonOptix MyoCam system (IonOptix Corporation, Milton, MA, USA). Total and phosphorylated Akt were evaluated using western blot analysis. 3. Female mouse myocytes displayed smaller peak shortening (PS) amplitude and maximal velocity of shortening/relengthening (+/-dL/dt), longer time to PS and time to 90% relengthening compared with male counterparts. Diabetes significantly reduced PS, +/-dL/dt, prolonged TR(90), delayed intracellular Ca(2+) clearing and reduced sarcoplasmic reticulum (SR) Ca(2+) release in male mouse myocytes. All these abnormalities, with the exception of SR Ca(2+), release were masked by the female gender. 4. The negative staircase of PS with increased stimulus frequency (from 0.1 to 5.0 Hz) and protein carbonyl damage were comparable among all animal groups. 5. Female gender and diabetes independently enhanced phosphorylation of Akt without affecting total Akt expression. Interestingly, STZ-induced short-term diabetes failed to elicit additional phosphorylation of Akt in female hearts. 6. In summary, the present data revealed that STZ induced impaired cardiac contractile function and altered intracellular Ca(2+) handling in males, but not females, partially due to intrinsic mechanical differences and Akt activation status between genders.