Hypoxia-activated platelets stimulate proliferation and migration of pulmonary arterial smooth muscle cells by phosphatidylserine/LOX-1 signaling-impelled intercellular communication
Hypoxia-activated platelets stimulate proliferation and migration of pulmonary arterial smooth muscle cells by phosphatidylserine/LOX-1 signaling-impelled intercellular communication
复制标题
缺氧激活的血小板通过磷脂酰丝氨酸/LOX-1信号驱动的细胞间通讯刺激肺动脉平滑肌细胞的增殖和迁移
DOI：
10.1016/j.cellsig.2021.110149
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发表时间：
2021-09-25
影响因子：
4.8
通讯作者：
Hu，Changping
中科院分区：
文献类型：
--
作者：
Ge，Xiaoyue;Zhang，Weifang;Hu，Changping
在肺动脉高压(PH)中，血小板的持续募集和不适当的激活参与了肺血管重构。我们先前的研究表明，凝集素样氧化型低密度脂蛋白受体-1(LOX-1)调节肺动脉平滑肌细胞(PASMCs)的增殖。暴露在活化的血小板表面的磷脂酰丝氨酸是LOX-1的配体。然而，低氧激活的血小板是否通过磷脂酰丝氨酸/LOX-1信号驱动的细胞间通讯刺激PASMCs的增殖和迁移仍不清楚。本研究发现，低氧(10%O2)处理21天的大鼠出现了肺动脉高压，表现为血小板的激活和在肺动脉中的聚集，LOX-1基因敲除抑制了低氧诱导的肺动脉高压和血小板的激活。值得注意的是，PASMCs与低氧PH大鼠来源的血小板共同孵育可上调PASMCs中LOX-1的表达，导致PASMCs的增殖和迁移，这一作用可被磷脂酰丝氨酸抑制剂Annexin V或LOX-1中和抗体抑制。LOX-1基因敲除导致低氧激活的血小板刺激的PASMCs增殖和迁移减少。低氧可上调大鼠肺血管信号转导和转录激活子3(STAT3)的磷酸化及Pim-1的表达。低氧激活的血小板还上调PASMCs中STAT3的磷酸化和Pim-1的表达，这种上调可被Annexin V、LOX-1中和抗体、蛋白激酶C抑制剂和LOX-1基因敲除所抑制。总之，我们首次证明低氧激活的血小板通过磷脂酰丝氨酸/LOX-1/PKC/STAT3/Pim-1信号驱动的细胞间通讯刺激PASMCs的增殖和迁移，从而潜在地促进缺氧性肺血管重建。
Continuous recruitment and inappropriate activation of platelets in pulmonary arteries contribute to pulmonary vascular remodeling in pulmonary hypertension (PH). Our previous study has demonstrated that lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) regulates the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Phosphatidylserine exposed on the surface of activated platelets is a ligand for LOX-1. However, whether hypoxia-activated platelets stimulate the proliferation and migration of PASMCs by phosphatidylserine/LOX-1 signaling-impelled intercellular communication remains unclear. The present study found that rats treated with hypoxia (10% O2) for 21 days revealed PH with the activation of platelets and the recruitment of platelets in pulmonary arteries, and LOX-1 knockout inhibited hypoxia-induced PH and platelets activation. Notably, co-incubation of PASMCs with hypoxic PH rats-derived platelets up-regulated LOX-1 expression in PASMCs leading to the proliferation and migration of PASMCs, which was inhibited by the phosphatidylserine inhibitor annexin V or the LOX-1 neutralizing antibody. LOX-1 knockout led to decreased proliferation and migration of PASMCs stimulated by hypoxia-activated platelets. In rats, hypoxia up-regulated the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and the expression of Pim-1 in pulmonary arteries. Hypoxia-activated platelets also up-regulated the phosphorylation of Stat3 and the expression of Pim-1 in PASMCs, which was inhibited by annexin V, the LOX-1 neutralizing antibody, the protein kinase C inhibitor and LOX-1 knockout. In conclusion, we for the first time demonstrated that hypoxia-activated platelets stimulated the proliferation and migration of PASMCs by phosphatidylserine/LOX-1/PKC/Stat3/Pim-1 signaling-impelled intercellular communication, thereby potentially contributing to hypoxic pulmonary vascular remodeling.