Department of Pharmacology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea.
Division of Cardiovascular Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, 187 Osongsaengmyeng 2-ro, Osong-eub, Heungdeok-gu, Cheongju-si 28159, Republic of Korea.
Int J Mol Sci. 2023 Apr 30;24(9):8094. doi: 10.3390/ijms24098094.
Platelet-derived growth factor type BB (PDGF-BB) regulates vascular smooth muscle cell (VSMC) migration and proliferation, which play critical roles in the development of vascular conditions. p90 ribosomal S6 kinase (p90RSK) can regulate various cellular processes through many different target substrates in several cell types, but the regulatory function of p90RSK on PDGF-BB-mediated cell migration and proliferation and subsequent vascular neointima formation has not yet been extensively examined. In this study, we investigated whether p90RSK inhibition protects VSMCs against PDGF-BB-induced cellular phenotypic changes and the molecular mechanisms underlying the effect of p90RSK inhibition on neointimal hyperplasia in vivo. Pretreatment of cultured primary rat VSMCs with FMK or BI-D1870, which are specific inhibitors of p90RSK, suppressed PDGF-BB-induced phenotypic changes, including migration, proliferation, and extracellular matrix accumulation, in VSMCs. Additionally, FMK and BI-D1870 repressed the PDGF-BB-induced upregulation of cyclin D1 and cyclin-dependent kinase-4 expression. Furthermore, p90RSK inhibition hindered the inhibitory effect of PDGF-BB on Cdk inhibitor p27 expression, indicating that p90RSK may induce VSMC proliferation by regulating the G0/G1 phase. Notably, treatment with FMK resulted in attenuation of neointima development in ligated carotid arteries in mice. The findings imply that p90RSK inhibition mitigates the phenotypic switch and neointimal hyperplasia induced by PDGF-BB.
血小板衍生生长因子 BB（PDGF-BB）调节血管平滑肌细胞（VSMC）迁移和增殖，这在血管疾病的发展中起着关键作用。p90 核糖体 S6 激酶（p90RSK）可以通过多种不同的靶底物在多种细胞类型中调节各种细胞过程，但 p90RSK 对 PDGF-BB 介导的细胞迁移和增殖以及随后的血管新生内膜形成的调节功能尚未得到广泛研究。在这项研究中，我们研究了 p90RSK 抑制是否可以保护 VSMC 免受 PDGF-BB 诱导的细胞表型变化，以及 p90RSK 抑制对体内新生内膜增生的影响的分子机制。用 FMK 或 BI-D1870（p90RSK 的特异性抑制剂）预处理培养的原代大鼠 VSMC，可抑制 PDGF-BB 诱导的 VSMC 表型变化，包括迁移、增殖和细胞外基质积累。此外，FMK 和 BI-D1870 抑制了 PDGF-BB 诱导的 cyclin D1 和 cyclin-dependent kinase-4 表达上调。此外，p90RSK 抑制阻碍了 PDGF-BB 对 Cdk 抑制剂 p27 表达的抑制作用，表明 p90RSK 可能通过调节 G0/G1 期来诱导 VSMC 增殖。值得注意的是，用 FMK 处理可减轻小鼠结扎颈动脉中的新生内膜形成。这些发现表明，p90RSK 抑制减轻了 PDGF-BB 诱导的表型转换和新生内膜增生。
