Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Cell Stress Chaperones. 2020 May;25(3):455-466. doi: 10.1007/s12192-020-01086-0. Epub 2020 Mar 27.
Endothelial cells play essential roles in angiogenesis. Heat shock protein A12B (HSPA12B), a novel member of the multigene Hsp70 family, expresses specifically in endothelial cells. Alpha-lipoic acid (LA) has been used for the treatment of human diabetic complications for more than 20 years. However, little is known whether LA impacts endothelial proliferation and migration. To address these questions, primary human umbilical vein endothelial cells (HUVECs) were isolated and treated with LA. We found that LA reduced viable HUVECs but not caused LDH leakage and nuclear condensation, suggesting an inhibitory effect of LA on HUVEC proliferation. We also noticed that LA impeded wound closure of HUVEC monolayers. The expressions of C-Myc, VEGF, and eNOS and phosphorylation of focal adhesion kinase were reduced by LA. Moreover, LA decreased the expression of heat shock protein A12B (HSPA12B). Notably, overexpression of HSPA12B in endothelial cells prevented the LA-induced loss of VEGF. More importantly, HSPA12B overexpression attenuated the LA-induced inhibition of endothelial proliferation and migration. Collectively, the results demonstrated that LA inhibited proliferative and migratory abilities in human vascular endothelial cells through the downregulation of the HSPA12B/VEGF signaling axis. The data suggest that besides the treatment in diabetic complications, LA might represent a viable therapeutic potential for human diseases that involve high angiogenic activities such as cancers.
内皮细胞在血管生成中发挥着重要作用。热休克蛋白 A12B（HSPA12B）是多基因 Hsp70 家族的新成员，特异性表达于内皮细胞。α-硫辛酸（LA）已被用于治疗人类糖尿病并发症超过 20 年。然而，对于 LA 是否影响内皮细胞的增殖和迁移知之甚少。为了解决这些问题，我们分离了原代人脐静脉内皮细胞（HUVECs）并用 LA 进行处理。我们发现 LA 减少了有活力的 HUVECs，但没有导致 LDH 漏出和核浓缩，这表明 LA 对 HUVEC 增殖有抑制作用。我们还注意到 LA 阻碍了 HUVEC 单层的伤口闭合。LA 降低了 C-Myc、VEGF 和 eNOS 的表达以及黏着斑激酶的磷酸化。此外，LA 降低了热休克蛋白 A12B（HSPA12B）的表达。值得注意的是，内皮细胞中 HSPA12B 的过表达阻止了 LA 诱导的 VEGF 丧失。更重要的是，HSPA12B 的过表达减弱了 LA 诱导的内皮细胞增殖和迁移抑制。总之，这些结果表明，LA 通过下调 HSPA12B/VEGF 信号轴抑制了人血管内皮细胞的增殖和迁移能力。这些数据表明，除了治疗糖尿病并发症外，LA 可能代表着一种有前途的治疗方法，可用于涉及高血管生成活性的人类疾病，如癌症。
