Disruption of calcium homeostasis by cardiac-specific over-expression of PPAR-γ in mice: A role in ventricular arrhythmia

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• 作者：Yong Xie ; Ph.D ; MD^a ; ^b ; ¹ ; Zhen-Jie Gu ; Master ; MD^a ; ^b ; ¹ ; Mao-Xiong Wu ; Master ; MD^a ; ^b ; ¹ ; Tu-Cheng Huang ; Master ; MD^a ; ^b ; Jing-Song Ou ; Ph.D ; MD^c ; ^d ; ^e ; Huiping-Son Ni ; Ph.D^f ; Mao-Huan Lin ; Ph.D ; MD^a ; ^b ; Wo-Liang Yuan ; Ph.D ; MD^a ; ^b ; Jing-Feng Wang ; Ph.D ; MD^a ; ^b ; ^{dr_wjf@hotmail.com} ; Yang-Xin Chen ; Ph.D ; MD^a ; ^b ; ^{tjcyx1995@163.com}
• 关键词：PPAR-γ overexpression ; Calcium homeostasis ; Calcium regulatory proteins ; Ventricular arrhythmia
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：167
• 期：Complete
• 页码：12-21
• 全文大小：1850 K
• 卷排序：167

文摘

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.Materials and methodsCardiac 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.Key findingsIn 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.SignificancePPAR-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.