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

Xie, Yong, Gu, Zhen-Jie, Wu, Mao-Xiong, Huang, Tu-Cheng, Ou, Jing-Song, Ni, Huiping-Son, Lin, Mao-Huan, Yuan, Wo-Liang, Wang, Jing-Feng, Chen, Yang-Xin
Life sciences 2016 v.167 pp. 12-21
calcium, calcium-calmodulin-dependent protein kinase, cardiomyocytes, confocal microscopy, death, flow cytometry, gene overexpression, homeostasis, humans, mice, regulatory proteins, sarcoplasmic reticulum, tachycardia, transgenic animals
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.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.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.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.