title: Calcium-sensing receptors induce apoptosis in rat cardiomyocytes via the endo(sarco)plasmic reticulum pathway during hypoxia/reoxygenation.
abstract: The calcium-sensing receptor (CaR) is a G protein-coupled receptor. The CaR stimulation elicits phospholipase C-mediated inositol triphosphate formation, leading to an elevation in the level of intracellular calcium released from endoplasmic reticulum (ER). Depletion of ER Ca(2+) leads to ER stress, which is thought to induce apoptosis. Intracellular calcium overload-induced apoptosis in cardiac myocytes during hypoxia-reoxygenation (H/Re) has been demonstrated. However, the links between CaR, ER stress and apoptosis during H/Re are unclear. This study hypothesized that the CaR could induce apoptosis in neonatal rat cardiomyocytes during H/Re via the ER stress pathway. Neonatal rat cardiomyocytes were subjected to 3 hr of hypoxia, followed by 6 hr of reoxygenation. CaR expression was elevated and the number of apoptotic cells was significantly increased, as shown by transferase-mediated dUTP nick end-labelling, with exposure to CaCl(2), a CaR activator, during H/Re. The intracellular calcium concentration was significantly elevated and the Ca(2+) concentration in the ER was dramatically decreased during H/Re with CaCl(2); both intracellular and ER calcium concentrations were detected by laser confocal microscopy. Expression of GRP78 (glucose-regulated protein 78), the cleavage products of ATF6 (activating transcription factor 6), phospho-PERK [pancreatic ER kinase (PKR)-like ER kinase], the activated fragments of caspase-12, and phospho-JNK (c-Jun NH(2)-terminal kinase) were increased following exposure to CaCl(2) during H/Re. Our results confirmed that the activated CaR can induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during H/Re.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Fanghao
authors.initials: F
authors.lastname: Lu
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Tian
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Bai
authors.forename: Huan
authors.initials: H
authors.lastname: Ren
authors.forename: He
authors.initials: H
authors.lastname: Chen
authors.forename: Xue
authors.initials: X
authors.lastname: Yu
authors.forename: Jingxiao
authors.initials: J
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D015687:Cell Hypoxia; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; D044169:Receptors, Calcium-Sensing; D048031:JNK Mitogen-Activated Protein Kinases; D053454:Caspase 12; D002118:Calcium