Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes:: Role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca2+ cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (+/- dL/dt) and intracellular Ca2+ fluorescence. Diabetes significantly depressed PS, +/- dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing, elevated resting intracellular Ca2+, reduced caffeine-induced sarcoplasmic reticulum Ca2+ release and dampened stress tolerance at high stimulus frequencies. NIT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase Subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na+-Ca2+ exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch. (c) 2005 Elsevier Inc. All rights reserved.