Disruption of calciumhomeostasis by cardiac-specific over-expression of PPAR-γ in mice: A role in ventricular arrhythmia
Disruption of calciumhomeostasis by cardiac-specific over-expression of PPAR-γ in mice: A role in ventricular arrhythmia
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小鼠心脏特异性 PPAR-γ 过度表达对钙稳态的破坏：在室性心律失常中的作用
DOI：
10.1016/j.lfs.2016.10.014
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发表时间：
2016-12-15
期刊：
影响因子：
6.1
通讯作者：
Chen, Yang-Xin
中科院分区：
文献类型：
--
作者：
Xie, Yong;Gu, Zhen-Jie;Chen, Yang-Xin
目的：在临床环境中观察到过氧化物酶体增殖物激活物受体-γ（PPAR-gamma）激活引起的心血管不良反应。但其潜在机制尚不清楚。现在，心脏特异性过氧化物酶体增殖物激活物受体γ过表达的转基因小鼠（TG-PPAR-gamma）来探讨其可能的机制。来自TG-PPAR-γ小鼠的心脏组织，一种过表达PPAR-γ的人心肌细胞系AC 16细胞，和PPAR-gamma激动剂处理的原代心肌细胞用于评估心肌钙调节蛋白作为肌浆网Ca 2+的表达ATP酶、Na+/Ca 2+交换器1、ryanodine受体2和受磷蛋白。细胞内Ca 2+水平也进行了检查，通过流式细胞仪和共聚焦显微镜与Fluo-4/AM在这些cells.Key发现：在这项研究中，频繁的室性早搏和多形性室性心动过速，观察TG-PPAR-γ，但不是在野生型小鼠。此外，我们发现TG-PPAR-γ小鼠、过表达PPAR-γ的人心肌细胞系AC 16细胞和PPAR-γ激动剂处理的原代心肌细胞中钙调节蛋白的表达分别高于对照组。此外，在PPAR-gamma过表达和PPAR-gamma激活组中，细胞内钙水平和CaMKII δ表达增加。抑制CaMKII δ可提高心肌细胞内钙水平，减少室性心律失常的发生。意义：PPAR-gamma过表达可扰乱心肌细胞内钙稳态，导致TG-PPAR-gamma小鼠室性心律失常和心脏性猝死。(C)2016 Elsevier Inc. All rights reserved.
Aims: Adverse cardiovascular effects induced by peroxisome proliferator activator receptor-gamma (PPAR-gamma) activation were observed in clinical setting. But the underlying mechanism is unclear. Now, transgenic mice with cardiac specific peroxisome proliferator activator receptor-gamma overexpression (TG-PPAR-gamma) were used to explore the possible mechanisms.Materials and methods: Cardiac tissues from TG-PPAR-gamma mice, a PPAR-gamma over-expressing human cardiomyocyte line AC16 cell, and PPAR-gamma 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 findings: In this study, frequent ventricular premature contraction and polymorphic ventricular tachycardia were observed in TG-PPAR-gamma but not in wild-type mice. Besides, we found the calcium regulatory proteins expression were higher in the TG-PPAR-gamma mice, PPAR-gamma overexpressing human cardiomyocyte line AC16 cell and PPAR-gamma agonist-treated primary cardiomyocytes than the control group respectively. In addition, an increase of intracellular calcium levels and CaMKII delta expression in PPAR-gamma overexpression and PPAR-gamma activation group. Moreover, Inhibition of CaMKII delta could improve the intracellular calciumlevels and reduce the occurrence of ventricular arrhythmia.Significance: PPAR-gamma over-expression perturbs the intracellular calcium homeostasis in cardiomyocytes which contribute to the ventricular arrhythmias and cardiac sudden death in TG-PPAR-gamma mice. (C) 2016 Elsevier Inc. All rights reserved.