Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Hypertension Research Institute of Jiangxi Province, Nanchang, Jiangxi, 330006, China.
Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Life Sci. 2023 Oct 1;330:122002. doi: 10.1016/j.lfs.2023.122002. Epub 2023 Aug 6.
Vascular smooth muscle cell (VSMC) proliferation and neointima formation play significant roles in atherosclerosis development and restenosis following percutaneous coronary intervention. Our team previously discovered that TEA domain transcription factor 1 (TEAD1) promotes vascular smooth muscle differentiation, which is necessary for vascular development. Conversely, aberrant YAP1 activation upregulates the platelet-derived growth factor receptor beta to encourage VSMC proliferation and neointima formation. In this study, we aimed to investigate the molecular mechanisms of YAP1/TEAD signaling during neointima formation. Our research focused on the prolyl 4-hydroxylase alpha 2 (P4HA2) and its downstream target, Yes-associated protein 1 (YAP1), in regulating VSMC differentiation and neointima formation. Our results indicated that P4HA2 reduction leads to VSMC dedifferentiation and promotes neointima formation after injury. Furthermore, we found that P4HA2-induced prolyl hydroxylation of YAP1 restricts its transcriptional activity, which is essential to maintaining VSMC differentiation. These findings suggest that targeting P4HA2-mediated prolyl hydroxylation of YAP1 may be a promising therapeutic approach to prevent injury-induced neointima formation in cardiovascular disease.
血管平滑肌细胞（VSMC）增殖和新生内膜形成在动脉粥样硬化发展和经皮冠状动脉介入治疗后的再狭窄中起重要作用。我们的团队之前发现，TEA 结构域转录因子 1（TEAD1）促进血管平滑肌分化，这对于血管发育是必要的。相反，异常的 YAP1 激活上调血小板衍生生长因子受体β，以鼓励 VSMC 增殖和新生内膜形成。在这项研究中，我们旨在研究 YAP1/TEAD 信号在新生内膜形成中的分子机制。我们的研究集中在脯氨酰 4-羟化酶α 2（P4HA2）及其下游靶标 Yes 相关蛋白 1（YAP1）在调节 VSMC 分化和新生内膜形成中的作用。我们的结果表明，P4HA2 的减少导致 VSMC 去分化，并促进损伤后的新生内膜形成。此外，我们发现 P4HA2 诱导的 YAP1 脯氨酰羟化限制了其转录活性，这对于维持 VSMC 分化至关重要。这些发现表明，靶向 P4HA2 介导的 YAP1 脯氨酰羟化可能是预防心血管疾病中损伤诱导的新生内膜形成的一种有前途的治疗方法。
