HMGB2诱导血管平滑肌细胞去分化促进动脉粥样硬化的机制研究

Dedifferentiation of vascular smooth muscle cells (VSMCs) is crucial for atherogenesis. We have collected atherosclerotic vessels and non-atherosclerotic vessels, and isolated the intima for mRNA microarray analysis. The results have shown that HMGB2 level is significantly increased in atherosclerotic tissue, as compared with non-atherosclerotic tissue, and that HMGB2 co-localizes with VSMC phenotype markers in plaque lesions. In vitro experiments, HMGB2 promotes lipid uptake, ROS production, inflammatory reactions, down-regulation of VSMC phenotype markers in a concentration-dependent manner, but macrophage phenotype markers are upregulated. Moreover, peritoneal injection of HMGB2 promotes atherogenesis in apoE-KO mice. We have further treated VSMCs with HMGB2 and oxLDL overnight, followed by mRNA microarray analysis. The results show that HMGB2 greatly upregulates α-catenin, PEDF, kallistatin, which are adverse modulator of Wnt/β-catenin pathway. After combining the data from previous studies and our findings, we speculate that HMGB2 promotes atherogenesis by repressing Wnt pathway activity to induce VSMCs dedifferentiation. In our future study, we will clarify the mechanism of HMGB2 promoting atherogensis via VSMCs dedifferentiation by using HMGB2-KO, HMGB2-Tg and wide-type mice, and administrating adenoviral β-catenin and pathway inhibitors.

血管平滑肌细胞（VSMCs）表型转分化是动脉粥样硬化发生的重要环节之一。我们对动脉粥样硬化和对照血管内层组织进行mRNA芯片分析，发现并证实前者组织中HMGB2水平显著升高，并与VSMCs分子标志共定位于同一区域。HMGB2剂量依赖性诱导VSMCs吞脂，促ROS生成、炎症增强、平滑肌细胞表型标志物降低，但巨噬细胞表型标志物增高。腹腔注射HMGB2重组蛋白促进apoE-KO小鼠动脉粥样硬化发生。mRNA芯片发现并证实，HMGB2上调Wnt/β-catenin通路的多种抑制性元素α-catenin、PEDF、kallistatin等。结合文献推断此为HMGB2诱导VSMCs去分化促动脉粥样硬化机制。后续将利用HMGB2-KO、HMGB2-Tg和对照小鼠，腺病毒和通路抑制剂等，从体内体外阐明HMGB2经过多途径下调Wnt/β-catenin通路诱导VSMCs表型转分化，促进动脉粥样硬化发生机制。

血管平滑肌细胞（VSMCs）表型转分化是动脉粥样硬化发生的重要环节之一。我们对动脉粥样硬化和对照血管内层组织进行mRNA芯片分析，发现并证实前者组织中HMGB2水平显著升高，并与VSMCs分子标志共定位于同一区域。HMGB2剂量依赖性诱导VSMCs吞脂，促ROS生成、炎症增强、平滑肌细胞表型标志物降低，但巨噬细胞表型标志物增高。腹腔注射HMGB2重组蛋白促进apoE-KO小鼠动脉粥样硬化发生。mRNA芯片发现并证实，HMGB2上调Wnt/β-catenin通路的多种抑制性元素α-catenin、PEDF、kallistatin等。对HMGB2-Tg/apoE KO小鼠给予β-catenin或ROS抑制剂干预后，体内体外实验证明小鼠动脉粥样硬化程度及得到逆转。