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

• DOI: 10.1016/j.lfs.2016.10.014
• Publication Date: 2016-10-17T01:11:33Z
• Authors: Yong Xie; Zhen-Jie Gu; Mao-Xiong Wu; Tu-Cheng Huang; Jing-Song Ou; Huiping-Son Ni; Mao-Huan Lin; Wo-Liang Yuan; Jing-Feng Wang; Yang-Xin Chen
• Keywords: 0301 basic medicine; Heart Ventricles; Arrhythmias, Cardiac; Mice, Transgenic; Calcium-Transporting ATPases; Cell Line; Up-Regulation; 3. Good health; Mice, Inbred C57BL; PPAR gamma; Mice; 03 medical and health sciences; Gene Expression Regulation; Animals; Homeostasis; Humans; Calcium; Myocytes, Cardiac; Cells, Cultured

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.