TY - JOUR
T1 - Calcium-sensing receptors induce apoptosis in rat cardiomyocytes via the endo(sarco)plasmic reticulum pathway during hypoxia/reoxygenation
AU - Lu, Fanghao
AU - Tian, Zhiliang
AU - Zhang, Weihua
AU - Zhao, Yajun
AU - Bai, Shuzhi
AU - Ren, Huan
AU - Chen, He
AU - Yu, Xue
AU - Wang, Jingxiao
AU - Wang, Lina
AU - Li, Hong
AU - Pan, Zhenwei
AU - Tian, Ye
AU - Yang, Baofeng
AU - Wang, Rui
AU - Xu, Changqing
PY - 2010/5
Y1 - 2010/5
N2 - 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 Ca2+ 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 CaCl2, a CaR activator, during H/Re. The intracellular calcium concentration was significantly elevated and the Ca2+ concentration in the ER was dramatically decreased during H/Re with CaCl2; 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 NH2-terminal kinase) were increased following exposure to CaCl2 during H/Re. Our results confirmed that the activated CaR can induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during H/Re.
AB - 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 Ca2+ 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 CaCl2, a CaR activator, during H/Re. The intracellular calcium concentration was significantly elevated and the Ca2+ concentration in the ER was dramatically decreased during H/Re with CaCl2; 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 NH2-terminal kinase) were increased following exposure to CaCl2 during H/Re. Our results confirmed that the activated CaR can induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during H/Re.
UR - http://www.scopus.com/inward/record.url?scp=77951038258&partnerID=8YFLogxK
U2 - 10.1111/j.1742-7843.2009.00502.x
DO - 10.1111/j.1742-7843.2009.00502.x
M3 - Article
C2 - 20030631
AN - SCOPUS:77951038258
SN - 1742-7835
VL - 106
SP - 396
EP - 405
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
IS - 5
ER -