Restoration of diabetes-induced abnormal local Ca2+release in cardiomyocytes by angiotensin II receptor blockade

Abstract

Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT1) and enhancement in PKC activity in the heart point out the role of AT1blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT1blocker, candesartan, on abnormal Ca2+release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6–8 h at 37°C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca2+transients, as well as depressed Ca2+loading of sarcoplasmic reticulum, basal Ca2+level, and spatiotemporal properties of the Ca2+sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT1receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca2+release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.