Edling Charlotte E, Fazmin Ibrahim T, Chadda Karan R, Ahmad Shiraz, Valli Haseeb, Huang Christopher L-H, Jeevaratnam Kamalan
Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.
Front Physiol. 2019 Apr 24;10:497. doi: 10.3389/fphys.2019.00497. eCollection 2019.
Deficiencies in the transcriptional co-activator, peroxisome proliferative activated receptor, gamma, coactivator-1β are implicated in deficient mitochondrial function. The latter accompanies clinical conditions including aging, physical inactivity, obesity, and diabetes. Recent electrophysiological studies reported that β mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes. They implicated impaired chronotropic responses to adrenergic challenge, compromised action potential (AP) generation and conduction despite normal AP recovery timecourses and background resting potentials, altered intracellular Ca homeostasis, and fibrotic change in the observed arrhythmogenicity.
We explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine β atria.
RNA isolated from murine atrial tissue samples from young (12-16 weeks) and aged (>52 weeks of age), wild type (WT) and mice were studied by pre-probed quantitative PCR array cards. We examined genes encoding sixty ion channels and other strategic atrial electrophysiological proteins. genotype independently reduced gene transcription underlying Na-K-ATPase, sarcoplasmic reticular Ca-ATPase, background K channel and cholinergic receptor function. Age independently decreased Na-K-ATPase and fibrotic markers. Both factors interacted to alter channel activity underlying atrial automaticity. However, neither factor, whether independently or interactively, affected transcription of cardiac Na, voltage-dependent K channels, surface or intracellular Ca channels. Nor were gap junction channels, β-adrenergic receptors or transforming growth factor-β affected.
These findings limit the possible roles of gene transcriptional changes in previously reported age-dependent pro-arrhythmic electrophysiologial changes observed in β atria to an altered Ca-ATPase () expression. This directly parallels previously reported arrhythmic mechanism associated with p21-activated kinase type 1 deficiency. This could add to contributions from the direct physiological outcomes of mitochondrial dysfunction, whether through reactive oxygen species (ROS) production or altered Ca homeostasis.
转录共激活因子过氧化物酶体增殖物激活受体γ辅激活因子1β的缺陷与线粒体功能缺陷有关。后者伴随着包括衰老、缺乏运动、肥胖和糖尿病在内的临床病症。最近的电生理研究报告称，β小鼠重现了临床年龄依赖性心房促心律失常表型。这些研究表明，尽管动作电位（AP）恢复时间进程和背景静息电位正常，但对肾上腺素能刺激的变时反应受损、AP产生和传导受损、细胞内钙稳态改变以及观察到的致心律失常性中的纤维化改变。
我们探讨了这些年龄依赖性生理变化与小鼠β心房基因转录改变的相关程度。
通过预探针定量PCR阵列卡研究从小鼠（12 - 16周）和老年（>52周龄）、野生型（WT）和β小鼠的心房组织样本中分离的RNA。我们检测了编码60种离子通道和其他重要心房电生理蛋白的基因。β基因型独立降低了钠钾ATP酶、肌浆网钙ATP酶、背景钾通道和胆碱能受体功能的基础基因转录。年龄独立降低钠钾ATP酶和纤维化标志物。这两个因素相互作用以改变心房自律性的通道活性。然而，无论是独立还是相互作用，这两个因素均未影响心脏钠通道、电压依赖性钾通道、表面或细胞内钙通道的转录。缝隙连接通道、β肾上腺素能受体或转化生长因子β也未受影响。
这些发现将先前报道的β心房中年龄依赖性促心律失常电生理变化中基因转录变化的可能作用限制为钙ATP酶（）表达改变。这与先前报道的与1型p21激活激酶缺乏相关的心律失常机制直接相似。这可能会增加线粒体功能障碍直接生理结果的影响，无论是通过活性氧（ROS）产生还是钙稳态改变。
