HOXA1 通过调节 NF-κB p65 和 KLF4 参与血管平滑肌细胞向巨噬细胞样细胞的转化：动脉粥样硬化发病机制的一个潜在机制。
HOXA1 participates in VSMC-to-macrophage-like cell transformation via regulation of NF-κB p65 and KLF4: a potential mechanism of atherosclerosis pathogenesis.
机构信息
Department of Vascular Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Harbin, 150001, Heilongjiang, China.
Department of General and Vascular Surgery, Shengjing Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
出版信息
Mol Med. 2023 Aug 1;29(1):104. doi: 10.1186/s10020-023-00685-8.
BACKGROUND
Macrophage-like transformation of vascular smooth muscle cells (VSMCs) is a risk factor of atherosclerosis (AS) progression. Transcription factor homeobox A1 (HOXA1) plays functional roles in differentiation and development. This study aims to explore the role of HOXA1 in VSMC transformation, thereby providing evidence for the potential mechanism of AS pathogenesis.
METHODS
High fat diet (HFD)-fed apolipoprotein E knockout (ApoE) mice were applied as an in vivo model to imitate AS, while 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POV-PC)-treated VSMCs were applied as an in vitro model. Recombinant adeno-associated-virus-1 (AAV-1) vectors that express short-hairpin RNAs targeting HOXA1, herein referred as AAV1-shHOXA1, were generated for the loss-of-function experiments throughout the study.
RESULTS
In the aortic root of AS mice, lipid deposition was severer and HOXA1 expression was higher than the wide-type mice fed with normal diet or HFD. Silencing of HOXA1 inhibited the AS-induced weight gain, inflammatory response, serum and liver lipid metabolism disorder and atherosclerotic plaque formation. Besides, lesions from AS mice with HOXA1 knockdown showed less trans-differentiation of VSMCs to macrophage-like cells, along with a suppression of krüppel-like factor 4 (KLF4) and nuclear factor (NF)-κB RelA (p65) expression. In vitro experiments consistently confirmed that HOXA1 knockdown suppressed lipid accumulation, VSMC-to-macrophage phenotypic switch and inflammation in POV-PC-treated VSMCs. Mechanism investigations further illustrated that HOXA1 transcriptionally activated RelA and KLF4 to participate in the pathological manifestations of VSMCs.
CONCLUSIONS
HOXA1 participates in AS progression by regulating VSMCs plasticity via regulation of NF-κB p65 and KLF4. HOXA1 has the potential to be a biomarker or therapeutic target for AS.
背景
血管平滑肌细胞（VSMC）的巨噬细胞样转化是动脉粥样硬化（AS）进展的危险因素。转录因子同源盒 A1（HOXA1）在分化和发育中发挥功能作用。本研究旨在探讨 HOXA1 在 VSMC 转化中的作用，从而为 AS 发病机制的潜在机制提供证据。
方法
应用高脂饮食（HFD）喂养的载脂蛋白 E 敲除（ApoE）小鼠作为体内模型模拟 AS，同时应用 1-棕榈酰基-2-（5-氧代戊酰基）-sn-甘油-3-磷酸胆碱（POV-PC）处理的 VSMC 作为体外模型。生成表达靶向 HOXA1 的短发夹 RNA 的重组腺相关病毒-1（AAV-1）载体，在此称为 AAV1-shHOXA1，用于整个研究中的功能丧失实验。
结果
在 AS 小鼠的主动脉根部，与正常饮食或 HFD 喂养的野生型小鼠相比，脂质沉积更严重，HOXA1 表达更高。沉默 HOXA1 抑制了 AS 诱导的体重增加、炎症反应、血清和肝脏脂质代谢紊乱以及动脉粥样硬化斑块形成。此外，HOXA1 敲低的 AS 小鼠病变中 VSMC 向巨噬细胞样细胞的转分化减少，同时抑制了 Kruppel 样因子 4（KLF4）和核因子（NF）-κB RelA（p65）的表达。体外实验一致证实，HOXA1 敲低抑制了 POV-PC 处理的 VSMC 中的脂质积累、VSMC 向巨噬细胞表型转换和炎症。机制研究进一步表明，HOXA1 通过调节 NF-κB p65 和 KLF4 转录激活 RelA 参与 VSMC 的病理表现。
结论
HOXA1 通过调节 NF-κB p65 和 KLF4 参与 VSMC 可塑性来参与 AS 的进展。HOXA1 有可能成为 AS 的生物标志物或治疗靶点。
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