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

Abstract

The defects identified in the mechanical activity of the hearts from type 1 diabetic animals include alteration of Ca 2؉ signaling via changes in critical processes that regulate intracellular Ca 2؉ concentration. These defects result partially from a dysfunction of cardiac ryanodine receptor calcium release channel (RyR2). The present study was designed to determine whether the properties of the Ca 2؉ sparks might provide insight into the role of RyR2 in the altered Ca 2؉ signaling in cardiomyocytes from diabetic animals when they were analyzed together with Ca 2؉ transients. Basal Ca 2؉ level as well as Ca 2؉ -spark frequency of cardiomyoctes isolated from 5-week streptozotocin (STZ)-induced diabetic rats significantly increased with respect to aged-matched control rats. Ca 2؉ transients exhibited significantly reduced amplitude and prolonged time courses as well as depressed Ca 2؉ loading of sarcoplasmic reticulum in diabetic rats. Spatio-temporal properties of the Ca 2؉ sparks in cardiomyocytes isolated from diabetic rats were also significantly altered to being almost parallel to the changes of Ca 2؉ transients. In addition, RyR2 from diabetic rat hearts were hyperphosphorylated and protein levels of both RyR2 and FKBP12.6 depleted. These data show that STZ-induced diabetic rat hearts exhibit altered local Ca 2؉ signaling with increased basal Ca 2؉ level.

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…This approach has abrogated the modulatory action of Ca 2+ transients on AP profile at different rates and has prevented the manifestation of destabilizing effects of spontaneous Ca 2+ releases on transmembrane potential. Enhanced diastolic Ca 2+ releases from the sarcoplasmic reticulum have been previously found in myocytes obtained from diabetic rats,67 suggesting that these spontaneous events may have contributed to the heterogeneity of electrical recovery observed in heart of STZ‐treated mice. Although these aspects represent important constraints to our study, we elected to initially dissect the contribution of ionic current remodeling on the electrical behavior of diabetic myocytes.…”

Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes

“…Phosphorylation of RyR S2808 has been associated with increased RyR open probability and SR Ca 2ϩ leak due to dissociation of the stabilizing protein FKBP1B (16,29). Phosphorylation of RyR S2808 has been found especially high in the context of hyperglycemia and diabetes (30,38,39). A Zn 2ϩ -dependent reduction in S2808 phosphorylation and subsequent reduction in SR Ca 2ϩ leak could explain the enhanced sensitivity of the hyperglycemic prediabetic rat cardiomyocyte to the relaxing effects reduced IBa recorded at Ϫ20 mV in a reversible manner.…”

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

“…Although alteration of Ca 2ϩ signaling via changes in critical processes that regulate intracellular Ca 2ϩ has become a hallmark of this type of cardiomyopathy, controversies, currently going on, relate to specific alterations in Ca 2ϩ signaling pathways contributing to the cardiac defects in diabetes (7,20). Recently, we reported that these defects result partially from altered local Ca 2ϩ signaling due to a dysfunction of cardiac PKA-mediated ryanodine receptor Ca 2ϩ release channel (RyR2) (51).…”

“…We and others have shown that chronic administration of ANG II receptor blockers could protect the heart from the development of cellular alterations typically related with diabetes (18,29,30,33,34). Although ANG II antagonism leads to an attenuation of the depressed SR-Ca 2ϩ -ATPase (SERCA) and to an improvement in intracellular Ca 2ϩ handling in heart failure (16,29), it is not known whether this antagonism can correct the defective interaction of RyR2 and FKBP12.6 that occurs in the SR during the development of diabetes-induced cardiomyopathy (51 …”

“…Most alterations were attributed to anomalous sarcoplasmic reticulum (SR) pump activity (15), SR-Ca 2ϩ storage (5), and partly to alterations in RyR2 properties (3,27,35,49,51). Recently, it has been shown that some cardioprotective agents correct the defective FK506 binding protein 12.6 (FKBP12.6)-mediated stabilization of RyR2, leading to an improvement in cardiac function of heart failure (29, 50).…”