Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

作者：Susanne U. Trost, Darrell D. Belke, Wolfgang F. Bluhm, Markus Meyer, Eric A. Swanson, WOLFGANG H. DILLMANN · 发表于：Diabetes · 年份：2002 · DOI：10.2337/diabetes.51.4.1166 · 被引用次数：265 · 研究领域：Cardiovascular Function and Risk Factors、Cardiac electrophysiology and arrhythmias、Cardiomyopathy and Myosin Studies

Diabetic cardiomyopathy is characterized by reduced cardiac contractility due to direct changes in heart muscle function independent of vascular disease. An important contributor to contractile dysfunction in the diabetic state is an impaired sarcoplasmic reticulum (SR) function, leading to disturbed intracellular calcium handling. We investigated whether overexpression of the SR calcium pump (SERCA2a) in transgenic mice could reduce the impact of diabetes on the development of cardiomyopathy. Diabetes was induced by streptozotocin injection (200 mg/kg), and left ventricular (LV) function was analyzed in isolated hearts 3 weeks later. In diabetic hearts systolic LV pressure was decreased by 15% and maximum speed of relaxation (-dP/dt) by 34%. Functional changes were also assessed in isolated papillary muscles. Active force was reduced by 61% and maximum speed of relaxation by 65% in the diabetic state. The contractile impairment was accompanied by a 30% decrease in SERCA2a protein in diabetic mice. We investigated whether increased SERCA2a expression in transgenic SERCA2a-overexpressing mice could compensate for the diabetes-induced decrease in cardiac function. Under normal conditions, SERCA2a overexpressors show improved contractile performance relative to wild-type (WT) mice (-dP/dt: 3,169 vs. 2,559 mmHg/s, respectively). Measurement of LV function in hearts from diabetic SERCA2a mice revealed systolic and diastolic functions that were similar to WT control mice and marked...