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

Abstract

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 markedly improved relative to diabetic WT mice (؊dP/dt: 2,534 vs. 1,690 mmHg/s in diabetic SERCA2a vs. diabetic WT mice, respectively). Similarly, the contractile behavior of isolated papillary muscles from diabetic SERCA2a mice was not different from that of control mice. SERCA2a protein expression was higher (60%) in diabetic SERCA2a mice than WT diabetic mice. These results indicate that overexpression of SERCA2a can protect diabetic hearts from severe contractile dysfunction, presumably by improving the calcium sequestration of the SR.

Low-Dose T3 Replacement Restores Depressed Cardiac T3 Levels, Preserves Coronary Microvasculature and Attenuates Cardiac Dysfunction in Experimental Diabetes Mellitus

“…These responses appear to be present during the early stages of diabetic cardiac dysfunction and occur before signs of cardiac hypertrophy, LV dilation and fibrosis and systolic impairment as have been reported previously (3,4,29). Initiation of T 3 treatment during this early period of dysfunction preserves cardiac function and prevents the loss of the arteriolar resistance vessel network.…”

“…DM and hypothyroidism produce similar negative effects on cardiac function and are associated with impaired contractility (3,7,8,23), α to β myosin heavy chain (MHC) isoform shift (7,8,13,24), microvessel/blood flow abnormalities (4,13,(25)(26)(27), and dysregulation of Ca 2+ handling (23,(28)(29)(30)(31).…”

Manipulating Cardiac Contractility in Heart Failure

“…For example, overexpression of SERCA2 by transgenesis was protective against diabetic cardiomyopathy as well as cardiac dysfunction induced by chronic pressure overload. 55,56 Similarly, del Monte et al 57,58 showed that increased SERCA2 protein expression, or expression of an antisense phospholamban RNA, each improved contractile function of failing human ventricular myocytes in vitro. Moreover, adenovirus-mediated overexpression of SERCA2 in a pressure-overload rat model of heart failure produced a rescue in depressed cardiac function, myocardial energetics, and survival.…”

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

“…Several mechanisms are suggested for the pathogenesis of glucose-triggered cardiac dysfunction including prolonged action potential, impaired excitation-contraction coupling, loss of myofilament Ca 2+ sensitivity, elevated oxidative stress, intracellular Ca 2+ dysregulation and dampened insulin-like growth factor I (IGF-1) signaling (Cai & Kang 2001, Esberg & Ren 2003, Lagadic-Gossmann et al 1996, Ren 2000. Most of these speculations have received convincing support from clinical and experimental studies using antioxidant, gene delivery and IGF-1 as therapeutic remedies for cardiovascular complications in diabetes (Goo et al 1996, Ren et al 1999a, Trost et al 2002, Norby et al 2002. Nevertheless, the precise cellular signaling mechanism behind glucose toxicity-induced cardiac mechanical dysfunction and the therapeutic value of IGF-1 against hyperglycemia remains poorly understood.…”