title: Disruption of calcium homeostasis by cardiac-specific over-expression of PPAR-γ in mice: A role in ventricular arrhythmia.
abstract: OBJECTIVE
  Adverse cardiovascular effects induced by peroxisome proliferator activator receptor-γ (PPAR-γ) activation were observed in clinical setting. But the underlying mechanism is unclear. Now, transgenic mice with cardiac specific peroxisome proliferator activator receptor-γ overexpression (TG-PPAR-γ) were used to explore the possible mechanisms.
  
  
  METHODS
  Cardiac tissues from TG-PPAR-γ mice, a PPAR-γ over-expressing human cardiomyocyte line AC16 cell, and PPAR-γ agonist-treated primary cardiomyocytes were used to evaluate the expression of cardiac calcium regulatory proteins as sarcoplasmic reticulum Ca2+ATPase, Na+/Ca2+exchanger 1, ryanodine receptor 2 and phospholamban. Intracellular Ca2+levels were also examined by flow cytometry and confocal microscopy with Fluo-4/AM in these cells.
  
  
  RESULTS
  In this study, frequent ventricular premature contraction and polymorphic ventricular tachycardia were observed in TG-PPAR-γ but not in wild-type mice. Besides, we found the calcium regulatory proteins expression were higher in the TG-PPAR-γ mice, PPAR-γ overexpressing human cardiomyocyte line AC16 cell and PPAR-γ agonist-treated primary cardiomyocytes than the control group respectively. In addition, an increase of intracellular calcium levels and CaMKII δ expression in PPAR-γ overexpression and PPAR-γ activation group. Moreover, Inhibition of CaMKII δ could improve the intracellular calcium levels and reduce the occurrence of ventricular arrhythmia.
  
  
  CONCLUSIONS
  PPAR-γ over-expression perturbs the intracellular calcium homeostasis in cardiomyocytes which contribute to the ventricular arrhythmias and cardiac sudden death in TG-PPAR-γ mice.
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Zhen-Jie
authors.initials: ZJ
authors.lastname: Gu
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Mao-Xiong
authors.initials: MX
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Tu-Cheng
authors.initials: TC
authors.lastname: Huang
authors.affiliation: Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; The Key Laboratory of Assisted Circulation, Ministry of Health, China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, China.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Ou
authors.affiliation: Department of Preventive Medicine, Columbia University, New York, USA.
authors.forename: Huiping-Son
authors.initials: HS
authors.lastname: Ni
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Mao-Huan
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
authors.forename: Wo-Liang
authors.initials: WL
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China. Electronic address: dr_wjf@hotmail.com.
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China. Electronic address: tjcyx1995@163.com.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D047495:PPAR gamma; D000252:Calcium-Transporting ATPases; D002118:Calcium
keywords: Calcium homeostasis; Calcium regulatory proteins; PPAR-γ overexpression; Ventricular arrhythmia