Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China; School of Medicine, Shandong University, Jinan, China.
Department of Cardiology, Ju-ye People's Hospital, Heze, China.
Biochem Biophys Res Commun. 2020 Sep 3;529(4):998-1004. doi: 10.1016/j.bbrc.2020.06.075. Epub 2020 Jul 30.
Oxidized low-density lipoprotein (ox-LDL)-mediated NLRP3 inflammasome activation is crucial in atherosclerosis (AS) initiation and progression. Aldehyde dehydrogenase 2 (ALDH2) has been reported to display protective effects during AS development; however, the underlying mechanisms are largely unknown. Here we investigate the role of ALDH2 in ox-LDL-induced NLRP3 inflammasome priming and activation. We treated RAW264.7 murine macrophages with ox-LDL with or without ALDH2 activator Alda-1 and measured NLRP3 inflammasome priming and activation, ALDH2 protein expression and enzyme activity, IL-1β release, and DNA damage. It was found that ox-LDL impaired ALDH2 activity and induced NLRP3 inflammasome priming and activation. Alda-1 inhibited both of the priming and activation steps of NLRP3 inflammasome as well as subsequent cell pyroptosis and attenuated ROS and 4-HNE levels in ox-LDL-treated macrophages. Taken together, ALDH2 activation inhibits priming and activation of NLRP3 inflammasome via reducing oxidative stress, which suggests that ALDH2 may be a potential target for anti-inflammatory therapies in AS treatment.
氧化型低密度脂蛋白（ox-LDL）介导的 NLRP3 炎性小体激活在动脉粥样硬化（AS）的发生和发展中至关重要。醛脱氢酶 2（ALDH2）已被报道在 AS 发展过程中具有保护作用，但潜在机制尚不清楚。本研究旨在探讨 ALDH2 在 ox-LDL 诱导的 NLRP3 炎性小体的引发和激活中的作用。我们用 ox-LDL 处理 RAW264.7 小鼠巨噬细胞，并用或不用 ALDH2 激活剂 Alda-1 处理，并测量 NLRP3 炎性小体的引发和激活、ALDH2 蛋白表达和酶活性、IL-1β释放和 DNA 损伤。结果发现，ox-LDL 损害了 ALDH2 的活性，并诱导了 NLRP3 炎性小体的引发和激活。Alda-1 抑制了 NLRP3 炎性小体的引发和激活这两个步骤，以及随后的细胞焦亡，并减轻了 ox-LDL 处理的巨噬细胞中的 ROS 和 4-HNE 水平。综上所述，ALDH2 的激活通过减少氧化应激抑制了 NLRP3 炎性小体的引发和激活，这表明 ALDH2 可能是 AS 治疗中抗炎治疗的一个潜在靶点。
