OBJECTIVE Vascular endothelial cells (ECs) normally maintain vascular homeostasis and are regulated by proinflammatory cytokines and reactive oxygen species. A human genome-wide association study identified that AIP1 (ASK1 [apoptosis signal-regulating kinase 1]-interacting protein-1; also identified as DAB2IP) gene variants confer susceptibility to cardiovascular disease, but the underlying mechanism is unknown. Approach and Results: We detected a normal AIP1 form (named AIP1A) in the healthy aorta, but a shorter form of AIP1 (named AIP1B) was found in diseased aortae that contained atherosclerotic plaques and graft arteriosclerosis. AIP1B transcription in resting ECs was suppressed through epigenetic inhibition by RIF1 (Rap1 [ras-related protein 1]-interacting factor 1)/H3K9 (histone H3 lysine 9) methyltransferase-mediated H3K9 trimethylation, and this inhibition was released by proinflammatory cytokines. AIP1A, but not AIP1B, was downregulated by proteolytic degradation through a Smurf1 (SMAD [suppressor of mothers against decapentaplegic miscellaneous] ubiquitylation regulatory factor 1)-dependent pathway in ECs under inflammation. Therefore, AIP1B was the major form present during inflammatory conditions. AIP1B, which lacks the N-terminal pleckstrin homology domain of AIP1A, localized to the mitochondria and augmented TNFα (tumor necrosis factor alpha)-induced mitochondrial reactive oxygen species generation and EC activation. AIP1B-ECTG (EC-specific AIP1B transgenic) mice exhibited augmented reactive oxygen species production, EC activation, and neointima formation in vascular remodeling models. CONCLUSIONS Our current study suggests that a shift from anti-inflammatory AIP1A to proinflammatory AIP1B during chronic inflammation plays a key role in inflammatory vascular diseases.

中文翻译：

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短 AIP1（ASK1 相互作用蛋白 1）亚型定位于线粒体并促进血管功能障碍。

目的 血管内皮细胞（EC）通常维持血管稳态，并受到促炎细胞因子和活性氧的调节。一项人类全基因组关联研究发现，AIP1（ASK1 [凋亡信号调节激酶 1] 相互作用蛋白-1；也称为 DAB2IP）基因变异会导致心血管疾病的易感性，但其潜在机制尚不清楚。方法和结果：我们在健康主动脉中检测到了正常的 AIP1 形式（称为 AIP1A），但在含有动脉粥样硬化斑块和移植物动脉硬化的患病主动脉中发现了较短形式的 AIP1（称为 AIP1B）。静息 EC 中的 AIP1B 转录通过 RIF1（Rap1 [ras 相关蛋白 1] 相互作用因子 1）/H3K9（组蛋白 H3 赖氨酸 9）甲基转移酶介导的 H3K9 三甲基化的表观遗传抑制而受到抑制，并且这种抑制由促炎细胞因子释放。在炎症条件下的 EC 中，AIP1A（而非 AIP1B）通过 Smurf1（SMAD [母亲对十倍体麻痹杂项的抑制因子]泛素化调节因子 1）依赖性途径的蛋白水解降解而下调。因此，AIP1B 是炎症期间存在的主要形式。AIP1B 缺乏 AIP1A 的 N 端普莱克斯特林同源结构域，定位于线粒体并增强 TNFα（肿瘤坏死因子 α）诱导的线粒体活性氧生成和 EC 激活。AIP1B-ECTG（EC 特异性 AIP1B 转基因）小鼠在血管重塑模型中表现出活性氧产生增加、EC 激活和新内膜形成。结论 我们目前的研究表明，慢性炎症过程中从抗炎 AIP1A 到促炎 AIP1B 的转变在炎症性血管疾病中发挥着关键作用。