Saadeh Khalil, Chadda Karan R, Ahmad Shiraz, Valli Haseeb, Nanthakumar Nakulan, Fazmin Ibrahim T, Edling Charlotte E, Huang Christopher L-H, Jeevaratnam Kamalan
Faculty of Health and Medical Sciences, University of Surrey, GU2 7AL Guildford, United Kingdom.
School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
Mol Genet Metab Rep. 2021 Apr 9;27:100753. doi: 10.1016/j.ymgmr.2021.100753. eCollection 2021 Jun.
Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na-K ATPase activity (Atp1b1), surface Ca entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α ventricles. Western blotting revealed reduced Na1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.
肥胖和糖尿病等代谢紊乱所潜在的线粒体功能障碍与心律失常密切相关。小鼠Pgc-1α心脏可复制线粒体功能紊乱，并模拟相关的促心律失常电生理异常。采用定量PCR、蛋白质印迹法和组织学分析来研究与线粒体功能障碍相关的电生理变化的分子基础。qPCR分析表明，小鼠Pgc-1α心室中与钠钾ATP酶活性（Atp1b1）、表面钙内流（Cacna1c）、动作电位复极化（Kcnn1）、自主神经功能（Adra1d、Adcy4、Pde4d、Prkar2a）以及形态学特性（Myh6、Tbx3）相关的基因表达下调。蛋白质印迹法显示Na1.5表达降低，但Cx43表达正常。组织学分析显示Pgc-1α心室的组织纤维化增加。这些研究结果表明，在一组经过策略性选择的基因中，转录发生了改变，这些基因被确定为编码参与心脏电生理激活的蛋白质，因此可能与Pgc-1α缺乏相关的心律失常底物中的心室激活和钙稳态改变有关。它们补充并完善了之前关于Pgc-1缺陷小鼠心脏心房和心室中此类表达特征的研究。
