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Calcium‐Sensing Receptors Induce Apoptosis in Rat Cardiomyocytes via the Endo(sarco)plasmic Reticulum Pathway during Hypoxia/Reoxygenation
Author(s) -
Lu Fanghao,
Tian Zhiliang,
Zhang Weihua,
Zhao Yajun,
Bai Shuzhi,
Ren Huan,
Chen He,
Yu Xue,
Wang Jingxiao,
Wang Lina,
Li Hong,
Pan Zhenwei,
Tian Ye,
Yang Baofeng,
Wang Rui,
Xu Changqing
Publication year - 2010
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2009.00502.x
Subject(s) - endoplasmic reticulum , unfolded protein response , calcium in biology , apoptosis , calcium , atf6 , microbiology and biotechnology , caspase 12 , endocrinology , signal transduction , intracellular , medicine , chemistry , kinase , myocyte , biology , caspase , programmed cell death , biochemistry
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.