Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation

Abstract

Non-insulin-dependent diabetic (NIDD) male Wistar rats develop a cardiomyopathy approximately 9 mo after the onset of the diabetic condition. This cardiomyopathy is characterized by reduced contractility, relaxation, cardiac work, and diastolic compliance. Although the basis for these defects is not completely understood, altered cellular Ca2+ regulation appears to play a major role in their development. In both isolated sarcolemmal membrane and cardiomyocytes, significant diabetes-linked defects in Ca2+ metabolism were observed. A small, but significant, decrease in the rate of sarcolemmal ATP-dependent Ca2+ transport of the diabetic heart was observed. Also evident was a major defect in sarcolemmal Na(+)-Ca2+ exchange as determined by reduced Na(+)-dependent Ca2+ transport into vesicles and Na(+)-dependent Ca2+ efflux from 45Ca(2+)-loaded cardiomyocytes from diabetic rats. In isolated cardiomyocytes, it was observed that the relative fluorescence of fura-2 at 502 nm was higher in cells from NIDD hearts, suggestive of a higher cytosolic free Ca2+. Consistent with diabetes-linked defects in Ca(2+)-transporter activities, the accumulation of Ca2+ after depolarization with KCl was greater in the diabetic. This study demonstrates that diabetes-induced defects in Ca2+ movement by the various Ca2+ transporters lead to abnormal cytosolic Ca2+ regulation by the diabetic cardiomyocytes. This observation supports the notion that abnormal Ca2+ regulation contributes to the development of the NIDD cardiomyopathy.

Effects of Diabetes on Ryanodine Receptor Ca Release Channel (RyR2) and Ca2+ Homeostasis in Rat Heart

“…This is attributable to reduced sarcoplasmic reticulum Ca-ATPase and increased phospholamban expression (29,30) as well as to the anomalous RyR2 activity. These factors could also be responsible for the larger diastolic Ca 2ϩ level seen here in diabetic cells (31)(32)(33), although others reported no change (34,35) or even a decrease (36,37). However, this latter work (37) was performed using a low-Ca (0.5 mmol/l)-containing extracellular solution.…”

Rate-Dependent prolongation of action potential duration in single ventricular myocytes obtained from hearts of rats with streptozotocin-induced chronic diabetes sustained for 30–32 weeks

“…In chronic diabetic rats, elevation of intracellular Ca 2+ "concentrations has been observed with the use of a CaZ+-sensitive microelectrode [19] and with a fluorescent dye, fura-2 [20]; the contribution of calcium overload to diabetic cardiomyopathy was suggested. In addition, treatment with verapamil, a voltage-sensitive Ca 2+ channel blocker, improved cardiac dysfunction in STZ-induced diabetic rats [21].…”

Mechanisms of [Ca2+]i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice

“…By contrast, other well-known models of type 2 diabetes such as Otsuka Long Evans Tokushima Fatty rats (10) and db/db mice (11) present defects in both function and expression of SERCA. Streptozotocin injection in neonatal rats induces adult noninsulin-dependent diabetes, and the activities of plasmalemmal Ca 2ϩ ATPase (12,13) and Na ϩ /Ca 2ϩ exchanger (NCX) (13) are both decreased in this model. Thus, a distinct Ca 2ϩ transporter malfunction has been identified in different diabetic models, but an integrated mechanism of altered Ca 2ϩ homeostasis is lacking.…”