Defective intracellular Ca²⁺ signaling contributes to cardiomyopathy in Type 1 diabetic rats

Abstract

The goal of the study was to determine whether defects in intracellular Ca(2+) signaling contribute to cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Depression in cardiac systolic and diastolic function was traced from live diabetic rats to isolated individual myocytes. The depression in contraction and relaxation in myocytes was found in parallel with depression in the rise and decline of intracellular free Ca(2+) concentration ([Ca(2+)](i)). The sarcoplasmic reticulum (SR) Ca(2+) store and rates of Ca(2+) release and resequestration into SR were depressed in diabetic rat myocytes. The rate of Ca(2+) efflux via sarcolemmal Na(+)/Ca(2+) exchanger was also depressed. However, there was no change in the voltage-dependent L-type Ca(2+) channel current that triggers Ca(2+) release from the SR. The depression in SR function was associated with decreased SR Ca(2+)-ATPase and ryanodine receptor proteins and increased total and nonphosphorylated phospholamban proteins. The depression of Na(+)/Ca(2+) exchanger activity was associated with a decrease in its protein level. Thus it is concluded that defects in intracellular Ca(2+) signaling caused by alteration of expression and function of the proteins that regulate [Ca(2+)](i) contribute to cardiomyopathy in STZ-induced diabetic rats. The increase in phospholamban, decrease in Na(+)/Ca(2+) exchanger, and unchanged L-type Ca(2+) channel activity in this model of diabetic cardiomyopathy are distinct from other types of cardiomyopathy.

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…These alterations are the result of changes in the expression and function of SR Ca 2+ handling proteins; SERCA2a, NCX and RyR expressions are reduced, whereas phospholamban expression is increased and its phosphorylation decreased. As a consequence, SR Ca 2+ load is reduced, and SR Ca 2+ release and re-uptake are impaired [181,182]. Interestingly, an increased [184,185].…”

Insulin Resistance and Cardiomyopathy

“…The oxidative stress can impair glucose transport/utilization as well as mitochondrial ATP generation and intracellular Ca 2+ regulatory proteins. Abnormalities in Ca 2+ signaling/flux and myofilament functions, contribute to the cardiomyopathy changes and defective cardiac contractile function (86)(87). In the 1980s, Przyklenk K et al demonstrated that superoxide dismutase (SOD) plus catalase improve myocardial contractile function in the canine model (88).…”

Treinamento em natação atenua a disfução contrátil de cardiomiócitos de ratos diabéticos

“…The speed of contraction of cardiomyocytes is controlled by proteins that regulate intracellular Ca 2+ movement and the rate of ATP hydrolysis which, in turn, regulates the rate of formation of crossed bridges 21 . Cardiomyocytes of diabetic animals reduce the expression of regulatory proteins such as CaMKII, NCX, RyR2, SERCA2 and phospholamban (PLB) 5,7,15,[24][25][26] , which may delay the availability of Ca 2+ for cell contraction.…”

“…by SR, which helps to slow down cell relaxation 26 . These findings at the cellular level are consistent with the diastolic dysfunctions observed in diabetic hearts in vivo 7,11 .…”

“…The relaxation of cardiomyocytes depends on the removal of Ca 2+ from the cytosol to the SR (via SERCA2, PLB) to the extracellular medium (via NCX, sarcolemmal Ca 2+ ATPase) and to the mitochondria (via transport of mitochondrial Ca 2+ ) 21 . The expression and function of these cellular structures are reduced in cardiomyocytes of diabetic animals 12,[25][26][27][28] . This fact reduces the rate at which Ca 2+ is removed from the cytosol.…”