Pharmacological blockade of angiotensin II receptor restores diabetes-associated reduction of store operated Ca2+ entry in adult cardiomyocytes

Abstract

The store-operated Ca2+ entry (SOCE) represents an important route for generating cellular Ca2+ signals that are implicated in physiological and various pathological scenarios that include diabetic cardiomyopathy (DM-CMP) which is well known to have Ca2+ dysregulation among other salient features. In this study, we investigated the role of SOCE in Ca2+ handling of cardiomyocytes obtained from adult male Wistar rats that were made diabetic by intraperitoneal administration of streptozotocin (STZ 50 mg/kg). We also included another group of rats with diabetes induced by STZ administration but received an angiotensin II receptor blocker - losartan. In whole cell recordings with isolated cardiomyocytes, the SOCE-representative whole-cell current ICRAC was found to be significantly reduced for the diabetic group compared to the control group and chronic losartan treatment could restore ICRAC to a level comparable to the control group. However, in contrast to the observed reduction in ICRAC, Orai1 and Orai3 proteins were found to be significantly upregulated in diabetic condition whereas no significant change in the expression levels of Stim1, Stim2 and Orai2 was observed. Also, losartan treatment did not affect the expression pattern of these key proteins for SOCE in diabetic group. The observed imbalance between the functional read out of SOCE (peak ICRAC size) and expression levels of the underlying proteins was puzzling but could be, among other possibilities, due to impairment of interaction between Stim and Orai proteins. We argue that the observed changes in SOCE with diabetes could be a contributing factor for the Ca2+ dyshomeostasis associated with diabetic cardiomyopathies and blockade of angiotensin II receptor may potentially restore normal SOCE in diabetic cardiomyocytes.