心肌缺血早期致死性室性心律失常-心源性猝死的高发:应激与钙失衡交叉调节的关键作用

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xiaojuan Zhang, Mengxuan Zhang, Ye Zhang, Wei Zhang, Huishan Liang, Junyao Lv, Xudong Xiao, Guanghui Zhu, Xiaojun Yu, Minchao Lai, Dian Wang
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引用次数: 0

摘要

目的:早期心肌缺血(MI)易致死性室性心律失常(LVA)和随后的心源性猝死(SCD)。本研究旨在阐明氧化应激、内质网(ER)应激和钙(Ca2+)干扰在心肌梗死早期LVA-SCD风险增加中的交叉调节作用。结果:临床和动物模型数据均显示心肌梗死30分钟内SCD发生率较高。在心肌梗死动物中,在LVA发病前观察到t波交替和传导减慢。光学映射显示时空电生理不一致,包括LVA前动作电位和Ca2+瞬态的传导减慢和交替,在缺血发作后5-15分钟达到峰值,缺血区受影响最大。在发生LVA的离体心肌梗死心脏中观察到再入周期。SCD动物表现出线粒体和细胞质活性氧和Ca2+升高,线粒体损伤,内质网应激因子上调,Ca2+/钙调素依赖性蛋白激酶(氧化)-RyR2, ryanodine受体2 (CaMKII-RyR2)通路激活。这些结果在缺氧和营养不良的肌细胞中得到了部分验证。有针对性的干预措施,如MitoTEMPO减轻氧化应激,4-苯基丁酸抑制内质网应激,丹trolene或RyR2-S2814A抑制Ca2+泄漏,减弱干扰,降低SCD发病率。创新和结论:我们确定了心肌梗死后一个关键的30分钟窗口,在此期间,氧化还原/内质网应激和Ca2失衡通过CaMKII-RyR2途径协同驱动LVA和SCD。靶向这一途径可能为预防早期心肌梗死的LVA和SCD提供一种有希望的策略。氧化还原信号:00000 - 00000。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
High Incidence of Lethal Ventricular Arrhythmia-Sudden Cardiac Death in Early Myocardial Ischemia: Critical Roles of Cross-Regulation Between Stresses and Calcium Imbalance.

Aims: Early myocardial ischemia (MI) predisposes to lethal ventricular arrhythmias (LVA) and subsequent sudden cardiac death (SCD). This study aims to elucidate the roles of cross-regulation between oxidative stress, endoplasmic reticulum (ER) stress, and calcium (Ca2+) disturbances in the increased risk of LVA-SCD in early MI. Results: Both clinical and animal model data showed a higher incidence of SCD within 30 min of MI. In MI animals, T-wave alternans and conduction slowing were observed prior to LVA onset. Optical mapping revealed spatiotemporal electrophysiological discordances, including conduction slowing and alternans in both action potentials and Ca2+ transients before LVA, peaking 5-15 min after ischemia onset, with the ischemic zone most affected. Reentrant cycles were observed in isolated MI hearts that developed LVA. SCD animals exhibited elevated mitochondrial and cytosolic reactive oxygen species and Ca2+, mitochondrial damage, ER stressors upregulation, and activation of the Ca2+/calmodulin-dependent protein kinases (oxidized)-RyR2, ryanodine receptor 2 (CaMKII-RyR2) pathway. These results were partly validated in hypoxic and undernourished myocytes. Targeted interventions, such as MitoTEMPO to mitigate oxidative stress, 4-phenyl butyric acid to inhibit ER stress, and dantrolene or RyR2-S2814A to suppress Ca2+ leakage, attenuated disturbances and reduced SCD incidence. Innovation and Conclusion: We identify a critical 30-min window post-MI, during which redox/ER stress and Ca2 imbalance synergistically drive LVA and SCD via the CaMKII-RyR2 pathway. Targeting this pathway could offer a promising strategy to prevent LVA and SCD in early MI. Antioxid. Redox Signal. 00, 000-000.

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来源期刊
Antioxidants & redox signaling
Antioxidants & redox signaling 生物-内分泌学与代谢
CiteScore
14.10
自引率
1.50%
发文量
170
审稿时长
3-6 weeks
期刊介绍: Antioxidants & Redox Signaling (ARS) is the leading peer-reviewed journal dedicated to understanding the vital impact of oxygen and oxidation-reduction (redox) processes on human health and disease. The Journal explores key issues in genetic, pharmaceutical, and nutritional redox-based therapeutics. Cutting-edge research focuses on structural biology, stem cells, regenerative medicine, epigenetics, imaging, clinical outcomes, and preventive and therapeutic nutrition, among other areas. ARS has expanded to create two unique foci within one journal: ARS Discoveries and ARS Therapeutics. ARS Discoveries (24 issues) publishes the highest-caliber breakthroughs in basic and applied research. ARS Therapeutics (12 issues) is the first publication of its kind that will help enhance the entire field of redox biology by showcasing the potential of redox sciences to change health outcomes. ARS coverage includes: -ROS/RNS as messengers -Gaseous signal transducers -Hypoxia and tissue oxygenation -microRNA -Prokaryotic systems -Lessons from plant biology
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