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摘要
背景:缺血心脏过度释放去甲肾上腺素(NE)可引起严重且常致命性心律失常。常驻心脏肥大细胞合成和储存活性肾素,在脱颗粒时释放,导致局部心脏肾素-血管紧张素系统(RAS)激活,负责NE释放和随后的心律失常。已知由缺血/再灌注(I/R)的脂质过氧化(I/R)形成的有毒醛类物质可以使肥大细胞脱颗粒,并激活局部RAS。目的:探讨缺血预适应(IPC)及其受体在抗RAS心肌保护中的作用.方法:在离体条件下建立离体心肌、小鼠心脏I/R模型,体外培养人和小鼠肥大细胞株。结果:IPC不仅能显著减轻缺血后的损伤,而且能降低肥大细胞肾素的释放,从而起到抗RAS的心脏保护作用。同样,在肥大细胞表面表达的组胺-H4、腺苷-A3和鞘氨醇-1-磷酸-S1P1受体等Gicouded受体的激活,类似于IPC的抗心肌保护作用。这种作用的机制取决于蛋白激酶C、pkcε和线粒体醛脱氢酶2(ALDH 2)的特异性亚型的连续激活。ALDH 2酶活性的提高在抑制醛诱导的肥大细胞肾素释放、抑制RAS活化、减少NE释放和减轻再灌注心律失常中起着重要作用。结论:这些新发现的保护途径表明,肥大细胞Gicouded受体的激活和随后的ALDH 2磷酸化/激活是缓解RAS所致心脏功能障碍(包括缺血性心脏病和充血性心力衰竭)的一个新的治疗靶点。
关键词: 乙醛脱氢酶2型,GI偶联蛋白,缺血再灌注,缺血预处理,肥大细胞,去甲肾上腺素。
Current Medicinal Chemistry
Title:Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection
Volume: 25 Issue: 34
关键词: 乙醛脱氢酶2型,GI偶联蛋白,缺血再灌注,缺血预处理,肥大细胞,去甲肾上腺素。
摘要: Background: Excessive norepinephrine (NE) release in the ischemic heart elicits severe and often lethal arrhythmias. Resident cardiac mast cells synthesize and store active renin, which is released upon degranulation, causing the activation of a local cardiac renin-angiotensin system (RAS) responsible for NE release and consequent arrhythmias. Toxic aldehydes, known to be formed by lipid peroxidation in ischemia/reperfusion (I/R), have been shown to degranulate mast cells and activate a local RAS.
Objective: To provide an up-to-date description of the roles of ischemic preconditioning (IPC) and Gicoupled receptors in anti-RAS cardioprotection.
Methods: Ex-vivo I/R models in cavian and murine hearts, and human and murine mast cell lines in vitro.
Results: IPC not only drastically reduces the injury subsequent to a prolonged ischemic event, but also decreases mast cell renin release, thus affording anti-RAS cardioprotection. Similarly, activation of Gicoupled receptors, such as histamine-H4, adenosine-A3 and sphingosine-1-phosphate-S1P1 receptors, all expressed at the mast cell surface, mimic the cardioprotective anti-RAS effects of IPC. The mechanism of this action depends on the sequential activation of a specific isoform of protein kinase C, PKCε, and mitochondrial aldehyde dehydrogenase-type 2 (ALDH2). Increased ALDH2 enzymatic activity exerts a pivotal role in the sequential inhibition of aldehyde-induced mast-cell renin release, prevention of RAS activation, reduction of NE release and alleviation of reperfusion arrhythmias.
Conclusion: These recently discovered protective pathways indicate that activation of mast-cell Gicoupled receptors and subsequent ALDH2 phosphorylation/activation represent a novel therapeutic target for the alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.
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Cite this article as:
Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection, Current Medicinal Chemistry 2018; 25 (34) . https://dx.doi.org/10.2174/0929867325666180214115127
DOI https://dx.doi.org/10.2174/0929867325666180214115127 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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