Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility.
Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility.
复制标题
针对慢性疼痛相关心肌缺血易感性的 ALDH2 治疗干预
作者：
Li C;Sun W;Gu C;Yang Z;Quan N;Yang J;Shi Z;Yu L;Ma H
临床观察表明慢性疼痛和缺血性心脏病死亡率增加之间存在联系，但机制仍然难以捉摸。反应性醛类最近被证实为疼痛病理学的新参与者，而我们先前的研究表明，反应性醛类（4-HNE）诱导羰基应激，导致心肌缺血耐受。本研究的目的是探讨慢性疼痛是否会增加心肌缺血/再灌注（MI/R）损伤的易感性，并探讨潜在的机制，重点是有毒的醛和羰基应激。方法：采用慢性压迫背根神经节（CCD）的方法造成慢性疼痛。2周后，CCD、醛脱氢酶（ALDH 2）KO或野生型（WT）同窝小鼠随后经受体内MI/R。结果：在CCD-WT小鼠中，伤害感受增强与循环醛（4-HNE）积累和心脏蛋白质羰基化平行。从机制上讲，CCD诱导的4-HNE超负荷引起心脏Sirtuin 1（SIRT 1）羰基化失活，并抑制肝激酶B1（LKB 1）-AMP-活化蛋白激酶（LKB 1-AMPK）相互作用，导致MI/R损伤加重，死亡率高于非CCD WT小鼠。ALDH 2缺乏进一步加重CCD诱导的MI/R损伤易感性。外周组织中的外源性4-HNE暴露模拟慢性疼痛诱导的醛超负荷，引起持续性异常性疼痛和增加MI/R损伤。然而，通过AAV 9-cTNT介导的基因递送的心脏特异性ALDH 2上调显著改善了慢性疼痛诱导的SIRT 1羰基化失活并减少了MI/R损伤（较小的梗死面积、较少的凋亡和改善的心脏功能）。结论：总的来说，慢性疼痛增强的羰基应激通过SIRT 1羰基化失活和LKB 1-AMPK相互作用的损害促进心肌缺血不耐受。ALDH 2激活和蛋白质羰基化的预防可能是慢性疼痛患者心肌缺血易损性的潜在治疗靶点。我们的研究结果新提供了慢性疼痛和心肌功能障碍相互作用的重叠细胞机制。
Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive. Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance. The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress. Methods: Chronic pain was induced by chronic compression of the dorsal root ganglion (CCD). After 2 weeks CCD, aldehyde dehydrogenase (ALDH2) KO or wild-type (WT) littermate mice were then subjected to in vivo MI/R. Results: In CCD-WT mice, heightened nociception paralleled circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. Mechanistically, CCD-induced 4-HNE overload provoked cardiac Sirtuin 1 (SIRT1) carbonylative inactivation and inhibited Liver kinase B1 (LKB1) - AMP-activated protein kinase (LKB1-AMPK) interaction, which resulted in exacerbated MI/R injury and higher mortality compared with non-CCD WT mice. ALDH2 deficiency further aggravated CCD-induced susceptibility to MI/R injury. Exogenous 4-HNE exposure in peripheral tissue mimicked chronic pain-induced aldehyde overload, elicited sustained allodynia and increased MI/R injury. However, cardiac-specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly ameliorated chronic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and improved cardiac function). Conclusion: Collectively, chronic pain-enhanced carbonyl stress promotes myocardial ischemic intolerance by SIRT1 carbonylative inactivation and impairment of LKB1-AMPK interaction. ALDH2 activation and prevention of protein carbonylation may be a potential therapeutic target for myocardial ischemic vulnerability in chronic pain patients. Our results newly provided overlapping cellular mechanisms of chronic pain and myocardial dysfunction interplay.