The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2−/−ApoE−/− to ApoE−/− mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD.

中文翻译：

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ALDH2 缺乏通过 USP14-cGAS 依赖性促炎巨噬细胞极化加剧动脉粥样硬化


乙醛脱氢酶 2 (ALDH2) rs671 多态性普遍存在于东亚人群中，与心血管疾病 (CVD) 的高风险相关。然而，与 ALDH2 rs671 突变相关的高 CVD 背后的细胞和分子机制仍然难以捉摸。在这里，我们发现源自人 ALDH2 rs671 携带者和 ALDH2 敲除小鼠的巨噬细胞表现出增强的促炎巨噬细胞表型和受损的抗炎巨噬细胞表型。将 ALDH2−/−ApoE−/− 的骨髓移植到 ApoE−/− 小鼠体内显着增加了动脉粥样硬化斑块的生长和促炎巨噬细胞的极化。从机制上讲，ALDH2 抑制巨噬细胞中环 GMP-AMP 合酶 (cGAS)-干扰素基因刺激剂 (STING) 通路的激活。 RU.521 对 cGAS 的药理学抑制完全中和了 ALDH2 缺陷诱导的巨噬细胞极化。深入的机制研究表明，ALDH2 通过减少泛素特异性蛋白酶 14 (USP14) 和 cGAS 之间的相互作用，主要通过其减轻 4-羟基-2-壬烯醛的酶促作用，加速巨噬细胞中赖氨酸 282 处 cGAS K48 连接的多泛素化降解。 (4-HNE)积累。一致地，骨髓细胞中的 USP14 敲低减轻了巨噬细胞的促炎症反应并预防动脉粥样硬化。我们的研究结果为 ALDH2 缺乏相关的促炎症和动脉粥样硬化提供了新的机制见解，并为动脉粥样硬化相关的 CVD 的治疗提供了新的治疗和预防范例。