Kim Ji Won, Kim Ju Yeon, Bae Hee Eun, Kim Chi Dae
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea.
Korean J Physiol Pharmacol. 2024 Sep 1;28(5):449-456. doi: 10.4196/kjpp.2024.28.5.449.
Vascular smooth muscle cells (VSMCs) under biophysical stress play an active role in the progression of vascular inflammation, but the precise mechanisms are unclear. This study examined the cellular expression of monocyte chemoattractant protein 1 (MCP-1) and its related mechanisms using cultured rat aortic VSMCs stimulated with mechanical stretch (MS, equibiaxial cyclic stretch, 60 cycles/ min). When the cells were stimulated with 10% MS, MCP-1 expression was markedly increased compared to those in the cells stimulated with low MS intensity (3% or 5%). An enzyme-linked immunosorbent assay revealed an increase in HMGB1 released into culture media from the cells stimulated with 10% MS compared to those stimulated with 3% MS. A pretreatment with glycyrrhizin, a HMGB1 inhibitor, resulted in the marked attenuation of MCP-1 expression in the cells stimulated with 10% MS, suggesting a key role of HMGB1 on MCP-1 expression. Western blot analysis revealed higher PDGFR-α and PDGFR-β expression in the cells stimulated with 10% MS than 3% MS-stimulated cells. In the cells deficient of PDGFR-β using siRNA, but not PDGFR-α, HMGB1 released into culture media was significantly attenuated in the 10% MS-stimulated cells. Similarly, MCP-1 expression induced in 10% MS-stimulated cells was also attenuated in cells deficient of PDGFR-β. Overall, the PDGFR-β signaling plays a pivotal role in the increased expression of MCP-1 in VSMCs stressed with 10% MS. Therefore, targeting PDGFR-β signaling in VSMCs might be a promising therapeutic strategy for vascular complications in the vasculatures under excessive biophysical stress.
生物物理应激下的血管平滑肌细胞（VSMCs）在血管炎症进展中发挥着积极作用，但其确切机制尚不清楚。本研究使用经机械拉伸（MS，双轴循环拉伸，60次/分钟）刺激的培养大鼠主动脉VSMCs，检测单核细胞趋化蛋白1（MCP-1）的细胞表达及其相关机制。当细胞用10%的MS刺激时，与低MS强度（3%或5%）刺激的细胞相比，MCP-1表达明显增加。酶联免疫吸附测定显示，与3%MS刺激的细胞相比，10%MS刺激的细胞释放到培养基中的HMGB1增加。用HMGB1抑制剂甘草甜素预处理导致10%MS刺激的细胞中MCP-1表达明显减弱，表明HMGB1对MCP-1表达起关键作用。蛋白质印迹分析显示，10%MS刺激的细胞中PDGFR-α和PDGFR-β表达高于3%MS刺激的细胞。在使用小干扰RNA使PDGFR-β缺陷的细胞中，而不是PDGFR-α缺陷的细胞中，10%MS刺激的细胞释放到培养基中的HMGB1明显减少。同样，在PDGFR-β缺陷的细胞中，10%MS刺激的细胞中诱导的MCP-1表达也减弱。总体而言，PDGFR-β信号在10%MS应激VSMCs中MCP-1表达增加中起关键作用。因此，针对VSMCs中的PDGFR-β信号可能是治疗生物物理应激过度的脉管系统中血管并发症的一种有前景的治疗策略。
