Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
Department of Endocrinology and Metabolism, Tianjin Research Institute of Endocrinology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Nat Commun. 2024 Aug 27;15(1):7398. doi: 10.1038/s41467-024-51881-x.
Smooth muscle cell (SMC) phenotypic modulation, primarily driven by PDGFRβ signaling, is implicated in occlusive cardiovascular diseases. However, the promotive and restrictive regulation mechanism of PDGFRβ and the role of protein tyrosine phosphatase non-receptor type 14 (PTPN14) in neointimal hyperplasia remain unclear. Our study observes a marked upregulation of PTPN14 in SMCs during neointimal hyperplasia. PTPN14 overexpression exacerbates neointimal hyperplasia in a phosphatase activity-dependent manner, while SMC-specific deficiency of PTPN14 mitigates this process in mice. RNA-seq indicates that PTPN14 deficiency inhibits PDGFRβ signaling-induced SMC phenotypic modulation. Moreover, PTPN14 interacts with intracellular region of PDGFRβ and mediates its dephosphorylation on Y692 site. Phosphorylation of PDGFRβ negatively regulates PDGFRβ signaling activation. The levels of both PTPN14 and phospho-PDGFRβ are correlated with the degree of stenosis in human coronary arteries. Our findings suggest that PTPN14 serves as a critical modulator of SMCs, promoting neointimal hyperplasia. PDGFRβ, dephosphorylated by PTPN14, acts as a self-inhibitory site for controlling PDGFRβ activation.
平滑肌细胞（SMC）表型调节主要受 PDGFRβ 信号驱动，与闭塞性心血管疾病有关。然而，PDGFRβ的促进和抑制调节机制以及蛋白酪氨酸磷酸酶非受体型 14（PTPN14）在血管内膜增生中的作用尚不清楚。我们的研究观察到，在血管内膜增生过程中，SMC 中 PTPN14 的表达明显上调。PTPN14 的过表达以依赖于磷酸酶活性的方式加剧血管内膜增生，而 PTPN14 在 SMC 中的特异性缺失则减轻了这一过程。RNA-seq 表明，PTPN14 缺失抑制 PDGFRβ 信号诱导的 SMC 表型调节。此外，PTPN14 与 PDGFRβ的细胞内区域相互作用，并介导其在 Y692 位的去磷酸化。PDGFRβ 的磷酸化负调节 PDGFRβ 信号的激活。PTPN14 和磷酸化 PDGFRβ 的水平与人类冠状动脉狭窄的程度相关。我们的研究结果表明，PTPN14 作为 SMC 的关键调节因子，促进血管内膜增生。由 PTPN14 去磷酸化的 PDGFRβ 作为自身抑制性位点，控制 PDGFRβ 的激活。
