HMGB2激活YAP蛋白促进低氧诱导的肺动脉高压的机制研究

Enhanced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary hypertension, but its specific regulatory mechanism has not been fully elucidated. We observed that levels of HMGB2 increased in serum of pulmonary hypertension patients; HMGB2 expression was significantly elevated in lungs from chronic hypoxia–treated mice, while HMGB2 deletion reduced hypoxia-induced pulmonary vascular remodeling, and subsequently protected against hypoxia-induced pulmonary hypertension in mice; in primary PASMCs, HMGB2 treatment promoted proliferation and migration of PASMCs and induced YAP dephosphorylation and F-actin cytoskeleton formation. In addition, our previous studies have found HMGB2 may be a new ligand of RAGE. Therefore, we speculate that HMGB2/RAGE stimulation may act via downstream F-actin reorganization to suppress the Hippo/YAP pathway, thus leading to YAP activation, which mediates proliferation and migration of PASMCs and pulmonary vascular remodeling. In this proposal, we'll use HMGB2 knockout mice and HMGB2 overexpression knockin mice to establish the models of hypoxia and Su5416-induced pulmonary hypertension for analyzing the impact of HMGB2 on PASMC proliferation and migration, pulmonary vascular structure and pulmonary hypertension. Thus, from animal phenotype to cellular and molecular levels, we will systematically explore the detailed mechanism of HMGB2 involved in pulmonary vascular remodeling. We believe that this study will provide mechanistic basis for designing the new molecular targets to treat hypoxia-induced pulmonary hypertension.

肺动脉平滑肌细胞增殖和迁移增加在肺动脉高压（PH）肺血管重塑的病理生理过程中非常关键，但其具体分子调控机制尚不清楚。我们发现：PH患者血清HMGB2含量显著升高；在PH模型小鼠，肺组织HMGB2表达增加且HMGB2敲除显著减轻肺血管重塑和改善PH；在原代肺动脉平滑肌细胞中，HMGB2蛋白可促进细胞迁移和增殖、YAP蛋白去磷酸化及细胞骨架F-actin重组。另外，我们近期研究表明HMGB2可能是RAGE的新配体。据此，我们推测HMGB2经RAGE诱导F-actin重组来抑制Hippo/YAP通路，进而激活YAP蛋白以介导肺动脉平滑肌细胞迁移和增殖及肺血管重塑。我们将以HMGB2敲除小鼠、过表达定点敲入小鼠为研究对象，建立PH模型，观察HMGB2对肺动脉平滑肌细胞迁移和增殖、肺血管结构和PH的影响，从动物表型到细胞分子水平系统解析HMGB2参与肺血管重塑的详细机制，为PH治疗提供新的分子靶点。

肺动脉平滑肌细胞增殖和迁移增加在肺动脉高压（PH）肺血管重塑的病理生理过程中非常关键，但其具体分子调控机制尚不清楚。寻找调控平滑肌细胞表型转化的干预靶点及分子机制是防治肺动脉高压肺血管重塑及外周血管重塑的关键。围绕上述关键问题，在本基金的资助下，我们主要在肺动脉高压肺血管重塑、平滑肌细胞表型转化及外周血管重塑等方向展开一系列研究，我们详细探究了HMGB2及DP1基因对肺动脉高压肺血管重塑进展的影响；HMGB2及DP1基因对肺动脉平滑肌细胞迁移及增殖的影响；HMGB2及DP1基因参与肺血管重塑及肺动脉平滑肌细胞迁移增殖的分子机制。在研究肺血管重塑过程中发现，OPG参与肺血管重塑的进展，我们进一步探究了OPG调控平滑肌细胞表型转化及外周血管重塑的分子机制。围绕上述研究内容，项目负责人在本基金的资助下，发现平滑肌细胞DP1基因特异性敲除可显著促进肺动脉高压进展及肺动脉平滑肌细胞肥大及增殖；分子机制方面，DP1受体敲除可使低氧诱导的肺动脉平滑肌细胞内mTORC1信号通路过度激活，进而调控肺动脉平滑肌细胞迁移和增殖及肺血管重塑；另外，我们发现临床治疗肺动脉高压靶向药物曲前列尼尔可特异性结合DP1受体，进而抑制mTORC1信号通路，改善肺动脉高压肺血管重塑及右心室肥厚。相关研究成果得到同领域权威专家特别述评，认为我们的研究为 mTORC1 抑制剂治疗肺动脉高压提供了进一步理论支持，同时为进一步探究曲前列尼尔与mTORC1抑制剂联合治疗肺动脉高压提供了潜在证据。在此基础上，我们进一步研究了OPG参与平滑肌细胞表型转化的分子机制，并阐明OPG可通过αvβ3激活YAP蛋白参与平滑肌细胞表型转化，提出干预OPG/YAP可能是防治血管重塑更为靶向的治疗策略。