title: Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure.
abstract: OBJECTIVE
  Alterations in calcium homeostasis in the intracellular endo/sarcoplasmic reticulum (ER/SR) and mitochondria of cardiomyocytes cause cell death via the SR and mitochondrial apoptotic pathway, contributing to ventricular dysfunction. However, the role of the calcium-sensing receptor (CaR) in cardiac hypertrophy and heart failure has not been studied. This study examined the possible involvement of CaR in the SR and mitochondrial apoptotic pathway in an experimental model of heart failure.
  
  
  RESULTS
  In Wistar rats, cardiac hypertrophy and heart failure were induced by subcutaneous injection of isoproterenol (Iso). Calindol, an activator of CaR, and calhex231, an inhibitor of CaR, were administered by caudal vein injection. Cardiac remodeling and left ventricular function were then analyzed in these rats. After 2, 4, 6 and 8 weeks after the administration of Iso, the rats developed cardiac hypertrophy and failure. The cardiac expression of ER chaperones and related apoptotic proteins was significantly increased in the failing hearts. Furthermore, the expression of ER chaperones and the apoptotic rate were also increased with the administration of calindol, whereas the expression of these proteins was reduced with the treatment of calhex231. We also induced cardiac hypertrophy and failure via thoracic aorta constriction (TAC) in mice. After 2 and 4 weeks of TAC, the expression of ER chaperones and apoptotic proteins were increased in the mouse hearts. Furthermore, Iso induced ER stress and apoptosis in cultured cardiomyocytes, while pretreatment with calhex231 prevented ER stress and protected the myocytes against apoptosis. To further investigate the effect of CaR on the concentration of intracellular calcium, the calcium concentration in the SR and mitochondria was determined with Fluo-5N and x-rhod-1 and the mitochondrial membrane potential was examined with JC-1 using laser confocal microscopy. After treatment with Iso for 48 hours, activation of CaR reduced [Ca(2+)]SR, increased [Ca(2+)]m, decreased the mitochondrial membrane potential, increased the expression of ER stress chaperones and related apoptotic proteins, and induced the release of cytochrome c from the mitochondria.
  
  
  CONCLUSIONS
  Our results demonstrated that CaR activation caused Ca(2+) release from the SR into the mitochondria and induced cardiomyocyte apoptosis through the SR and mitochondrial apoptotic pathway in failing hearts.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Fang-Hao
authors.initials: FH
authors.lastname: Lu
authors.forename: Song-Bin
authors.initials: SB
authors.lastname: Fu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Leng
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhang
authors.forename: Shiyun
authors.initials: S
authors.lastname: Dong
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Zhao
authors.forename: Huan
authors.initials: H
authors.lastname: Ren
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Zhong
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Xu
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D003514:Cyclohexylamines / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; D001549:Benzamides; D003514:Cyclohexylamines; D007211:Indoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018832:Molecular Chaperones; C482333:N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D045304:Cytochromes c; D007545:Isoproterenol; D002118:Calcium