title: Post-conditioning protecting rat cardiomyocytes from apoptosis via attenuating calcium-sensing receptor-induced endo(sarco)plasmic reticulum stress.
abstract: Our previous studies demonstrated that caclium-sensing receptor (CaR) stimulation elicited phospholipase C (PLC)-mediated inositol triphosphate (IP(3)) formation, leading to an elevation in [Ca(2+)](i) released from the endo(sarco)plasmic reticulum (ER) to induce ER stress and perturbations of ER function, which cause cardiomyocyte apoptosis during ischemia/reperfusion (I/R). The aim of this study was to determine whether the protection of post-conditioning (PC) from I/R heart injury involved relieving calcium-sensing receptor (CaR)-induced ER stress. Male Wistar rats were subjected to 30 min of ischemia followed by 2 h of reperfusion. The rats were post-conditioned after the 30 min of ischemia by three cycles of 10 s of reperfusion followed by 10 s of ischemia at the onset of reperfusion. Meanwhile, GdCl(3), an activator of CaR, and NPS-2390, a specific inhibitor, were administered. We found that the PC and PC with NPS-2390 groups improved the recovery of cardiac function during reperfusion compared to the IR and PC groups with GdCl(3), respectively. [Ca(2+)](i) and [Ca(2+)](ER) were determined using Fluo-4 AM and Fluo-5N AM, respectively, using laser confocal microscopy. [Ca(2+)](i) was significantly increased, whereas [Ca(2+)](ER) was significantly decreased in the I/R and PC groups with GdCl(3). The rate of apoptotic cells was significantly decreased as shown by TUNEL (Terminal deoxy-nucleotidyl transferase-mediated dUTP nick end labeling) assay in PC and PC with NPS-2390 groups compared to the I/R and PC groups with GdCl(3). In the I/R and PC groups with GdCl(3), the activated fragments of caspase-12, the cleavage products of activating transcription factor 6 (ATF6) and phospho-JNK (c-Jun NH(2)-terminal kinase) were increased compared to the PC and PC with GdCl(3) groups. These results demonstrated that PC could protect the myocardium from I/R injury by inhibiting CaR-induced sarcoplasmic reticulum stress.
authors: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors: Runtao
authors: R
authors: Gan
authors: Guangxia
authors: G
authors: Hu
authors: Yajun
authors: Y
authors: Zhao
authors: Hulun
authors: H
authors: Li
authors: Zhanfeng
authors: Z
authors: Jin
authors: Huan
authors: H
authors: Ren
authors: Shiyun
authors: S
authors: Dong
authors: Xin
authors: X
authors: Zhong
authors: Hongzhu
authors: H
authors: Li
authors: Baofeng
authors: B
authors: Yang
authors: Changqing
authors: C
authors: Xu
authors: Fanghao
authors: F
authors: Lu
authors: Weihua
authors: W
authors: Zhang
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D003331:Coronary Vessels; D059865:Endoplasmic Reticulum Stress; D005682:Gadolinium / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D057775:Ischemic Postconditioning; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011810:Quinoxalines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: C569355:2-quinoxaline-carboxamide-N-adamantan-1-yl; D011810:Quinoxalines; D044169:Receptors, Calcium-Sensing; D008315:Malondialdehyde; D005682:Gadolinium; D007770:L-Lactate Dehydrogenase; C038958:gadolinium chloride; D000218:Adamantane; D002118:Calcium