Ageing Increases Cardiac Electrical Remodelling in Rats and Mice via NOX4/ROS/CaMKII-Mediated Calcium Signalling.
Ageing Increases Cardiac Electrical Remodelling in Rats and Mice via NOX4/ROS/CaMKII-Mediated Calcium Signalling.
复制标题
衰老通过 NOX4/ROS/CaMKII 介导的钙信号传导增加大鼠和小鼠的心脏电重塑。
DOI：
10.1155/2022/8538296
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发表时间：
2022
影响因子：
--
通讯作者：
Chen T
中科院分区：
文献类型：
--
作者：
Luo X;Yu W;Liu Z;Pu Z;Liu T;Li Y;Liu W;Lei M;Tan X;Chen T
老龄化是与心血管疾病有关的风险因素之一，包括心律失常和心力衰竭。与衰老相关的心功能障碍涉及一个复杂的病理生理过程。衰老心肌细胞膜电压和钙动力学异常可导致衰老相关的心律失常。然而，其潜在的机制还没有得到很好的阐明。这项研究包括幼年和老年大鼠或小鼠。通过心电图、超声心动图、体外心脏电压和钙离子光学标测评价心脏电生理特性和功能。用蛋白质组学、磷蛋白质组学、Western blotting、Masson染色和ROS测量来研究其潜在的机制。增龄增加了大鼠心肌肥大和纤维化的发生率。此外，年龄增加了由快速起搏和异丙肾上腺素(1 mg/kg I.P.)引起的室性心动过速或室颤的发生。在小鼠体内挑战。用双染料(膜电压(Vm)染料和细胞内钙离子染料)同时记录的光学标测显示，老化使Langendorff灌流的小鼠心脏的动作电位时程(APD)和钙瞬变时程(CaTD)延长，并使心室传导减慢。更重要的是，年龄增加了异丙肾上腺素诱发的APD80和CATD50的变化(1 μM)。Δ的APD80和Δ的CATD50。老化还通过将衰减时间常数从30%延长到90%来延缓钙瞬变的衰减(τ30−90)。此外，衰老还缩短了反映Vm/Ca~(2+)耦合的Vm/Ca~(2+)潜伏期，包括AP去极化中点与Ca~(2+)上升中点、跨膜电压峰值和胞浆钙峰值之间的耦合，以及50%电压复极化和胞浆钙排出的时间。光学标测还显示，老化增加了ISO诱发的心律失常的发生率和励磁转子的发生。大鼠心脏蛋白质组学和磷蛋白质组学分析表明，CaMKII参与了衰老诱导的蛋白和磷蛋白的变化。增龄增加ROS水平和NOX4、氧化型CaMKII(ox-CaMKII)、磷酸化CaMKII(p-CaMKII)和Periostin的表达。衰老通过NOX4/ROS/CaMKII途径介导的膜电压异常、细胞内钙处理和Vm/Ca~(2+)偶联，加速心脏重构，增加室性心律失常的易感性。
Ageing is one of the risk factors associated with cardiovascular diseases including cardiac arrhythmias and heart failure. Ageing-related cardiac dysfunction involves a complicated pathophysiological progress. Abnormal membrane voltage and Ca2+ dynamics in aged cardiomyocytes contribute to ageing-related arrhythmias. However, its underlying mechanisms have not been well clarified. Young and old rats or mice were included in this study. Cardiac electrophysiological properties and functions were assessed by ECG, echocardiography, and ex vivo heart voltage and Ca2+ optical mapping. Proteomics, phosphor-proteomics, Western blotting, Masson staining, and ROS measurement were used to investigate the underlying mechanisms. Ageing increased the incidence of cardiac hypertrophy and fibrosis in rats. Moreover, ageing increased the occurrence of ventricular tachycardia or ventricular fibrillation induced by rapid pacing and during isoprenaline (ISO) (1 mg/kg i.p.) challenge in mice in vivo. Optical mapping with dual dyes (membrane voltage (Vm) dye and intracellular Ca2+ dye) simultaneously recording revealed that ageing increased the action potential duration (APD) and Ca2+ transient duration (CaTD) and slowed the ventricular conduction with the Langendorff-perfused mouse heart. More importantly, ageing increased the ISO-induced (1 μM) changes of APD (ΔAPD80) and CaTD (ΔCaTD50). Ageing also delayed the decay of Ca2+ transient by extending the decay time constant from 30% to 90% (τ30−90). In addition, ageing decreased the Vm/Ca2+ latency which represented the coupling of Vm/Ca2+ including between the midpoint of AP depolarization and Ca2+ upstroke, peak transmembrane voltage and peak cytosolic calcium, and time to 50% voltage repolarization and extrusion of cytosolic calcium. Optical mapping also revealed that ageing increased the ISO-induced arrhythmia incidence and occurrence of the excitation rotor. Proteomics and phosphor-proteomics assays from rat hearts demonstrated ageing-induced protein and phosphor-protein changes, suggesting that CaMKII was involved in ageing-induced change. Ageing increased the level of ROS and the expression of NOX4, oxidative CaMKII (ox-CaMKII), phosphorated CaMKII (p-CaMKII), and periostin. Ageing accelerates cardiac remodelling and increases the susceptibility to ventricular arrhythmias through NOX4/ROS/CaMKII pathway-mediated abnormal membrane voltage and intracellular Ca2+ handling and Vm/Ca2+ coupling.
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影响因子：
5
作者：
Luczak, Elizabeth D.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.
影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
20.1
作者：
North BJ;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1111/j.1749-6632.1998.tb09905.x
发表时间：
1998-01-01
期刊：
TOWARDS PROLONGATION OF THE HEALTHY LIFE SPAN
影响因子：
--
作者：
Barja, G
通讯作者：
Barja, G
线粒体蛋白过度乙酰化导致小鼠射血分数保留的心力衰竭
影响因子：
5
作者：
Liu, Xin;Zhang, Yabing;Li, Tao
通讯作者：
Li, Tao