Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China; Academy of Integrative Medicine, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China.
Int Immunopharmacol. 2024 Jan 25;127:111313. doi: 10.1016/j.intimp.2023.111313. Epub 2023 Dec 21.
It is accepted that hypertension is a major, independent risk factor for atherosclerotic cardiovascular ischemic events, which are mainly attributed to the formation of unstable, vulnerable atherosclerotic lesions. But the mechanisms by which hypertension aggravates atherosclerosis (AS) through increased macrophage recruitment are unknown. It has been reported that TWIST1 can regulate the shear stress of blood flow in endothelial cells to promote the development of atherosclerosis, but the function of TWIST1 in macrophage recruitment during hypertension remains undefined. Here, the roles of TWIST1 in macrophage activation during N -nitro-l-arginine-methyl ester (L-NAME; NO-synthase (NOS) inhibitor)-induced hypertension were investigated in ApoE mice fed a high-fat diet (HFD) and RAW264.7 cells treated with oxidized low-density lipoprotein(ox-LDL). Oil Red O staining and hematoxylin and eosin staining were adopted to analyze atherosclerotic lesions and plaque instability. Chromatin immunoprecipitation (ChIP)-PCR was used to explore whether Lysine-specific histone demethylase 1A (LSD1/KDM1A) and Variegated suppressor 3-9 homolog 1 (SUV39H1) could regulate histone modification of the TWIST1 promoter. We reported that L-NAME increased the expression of TWIST1 in the aortic tissues of ApoE mice fed a high-fat diet (HFD) and RAW264.7 cells treated with ox-LDL. TWIST1 accelerated the development of an unstable atherosclerotic phenotype by promoting macrophage activation, inflammatory factor secretion, macrophage polarization, and lipid phagocytosis. Moreover, we found that H3K9me2 and H3K9me3 in the TWIST1 promoter could be coregulated by LSD1 and SUV39H1, and this process was modulated by CK2α. Taken together, these results revealed that TWIST1 in macrophages is a critical factor that mediates foam cell formation and enhances atherosclerotic plaque vulnerability during hypertension, and targeting TWIST1 may be a promising new therapeutic approach for delaying the progression of AS in hypertension.
人们普遍认为高血压是动脉粥样硬化性心血管缺血事件的一个主要的、独立的危险因素，这些缺血事件主要归因于不稳定、易损的动脉粥样硬化病变的形成。但是，高血压通过增加巨噬细胞募集来加重动脉粥样硬化（AS）的机制尚不清楚。据报道，TWIST1 可以调节内皮细胞中血流的切应力，从而促进动脉粥样硬化的发展，但 TWIST1 在高血压期间巨噬细胞募集中的功能仍未确定。在这里，研究了 TWIST1 在高脂饮食喂养的 ApoE 小鼠和用氧化型低密度脂蛋白（ox-LDL）处理的 RAW264.7 细胞中 N-硝基-L-精氨酸甲酯（L-NAME；NOS 抑制剂）诱导的高血压期间巨噬细胞激活中的作用。采用油红 O 染色和苏木精和伊红染色分析动脉粥样硬化病变和斑块不稳定性。染色质免疫沉淀（ChIP）-PCR 用于探索赖氨酸特异性组蛋白去甲基化酶 1A（LSD1/KDM1A）和变异抑制物 3-9 同源物 1（SUV39H1）是否可以调节 TWIST1 启动子的组蛋白修饰。我们报道 L-NAME 增加了高脂饮食喂养的 ApoE 小鼠的主动脉组织中 TWIST1 的表达（HFD）和 ox-LDL 处理的 RAW264.7 细胞。TWIST1 通过促进巨噬细胞活化、炎症因子分泌、巨噬细胞极化和脂质吞噬作用，加速不稳定的动脉粥样硬化表型的发展。此外，我们发现 TWIST1 启动子中的 H3K9me2 和 H3K9me3 可以由 LSD1 和 SUV39H1 共同调节，而这个过程是由 CK2α 调节的。总之，这些结果表明，巨噬细胞中的 TWIST1 是介导高血压期间泡沫细胞形成和增强动脉粥样硬化斑块脆弱性的关键因素，靶向 TWIST1 可能是一种有前途的新的治疗方法，可用于延缓高血压患者 AS 的进展。
