Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, State Key Laboratory of Radiation Medicine; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, State Key Laboratory of Radiation Medicine; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
Vascul Pharmacol. 2019 Jun;117:7-14. doi: 10.1016/j.vph.2018.06.003. Epub 2018 Jun 9.
Vascular endothelial protein tyrosine phosphatase (VE-PTP) is essential for endothelial cells (ECs) adherens junction and vascular homeostasis; however, the regulatory mechanism of VE-PTP transcription is unknown, and a drug able to promote VE-PTP expression in ECs has not yet been reported in the literature. In this study, we used human ECs as a model to explore small molecule compounds able to promote VE-PTP expression, and found that atorvastatin, a HMG-CoA reductase inhibitor widely used in the clinic to treat hypercholesterolemia-related cardiovascular diseases, strongly promoted VE-PTP transcription in ECs through activating the VE-PTP promoter and upregulating the expression of the transcription factor, specificity protein 1 (SP1). Additionally, atorvastatin markedly reduced VE-cadherin-Y731 phosphorylation induced by cigarette smoke extract and significantly enhanced stability of endothelial adherens junctions. Together, our findings reveal that atorvastatin up-regulates VE-PTP expression, increases VE-cadherin protein levels, and decreases VE-cadherin-Y731 phosphorylation to strengthen EC adherens junctions and maintain vascular cell monolayer integrity, offering a new mechanism of atorvastatin against CSE-induced disruption of vascular integrity and relevant cardio-cerebrovascular disease.
血管内皮蛋白酪氨酸磷酸酶（VE-PTP）对于内皮细胞（ECs）黏附连接和血管稳态至关重要；然而，VE-PTP 转录的调节机制尚不清楚，并且文献中尚未报道能够促进 ECs 中 VE-PTP 表达的药物。在这项研究中，我们使用人 ECs 作为模型来探索能够促进 VE-PTP 表达的小分子化合物，发现广泛用于治疗与高胆固醇血症相关的心血管疾病的 HMG-CoA 还原酶抑制剂阿托伐他汀通过激活 VE-PTP 启动子和上调转录因子特异性蛋白 1（SP1），强烈促进 ECs 中的 VE-PTP 转录。此外，阿托伐他汀显著降低了香烟烟雾提取物诱导的 VE-钙黏蛋白 Y731 磷酸化，并显著增强了内皮黏附连接的稳定性。总之，我们的研究结果表明，阿托伐他汀通过上调 VE-PTP 的表达、增加 VE-钙黏蛋白的蛋白水平以及降低 VE-钙黏蛋白 Y731 的磷酸化来增强 EC 黏附连接并维持血管细胞单层的完整性，为阿托伐他汀对抗 CSE 诱导的血管完整性破坏以及相关心脑血管疾病提供了新的机制。
