Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea.
College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
J Physiol Pharmacol. 2019 Apr;70(2). doi: 10.26402/jpp.2019.2.12. Epub 2019 Aug 20.
The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21/p27. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (HO) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.
血管平滑肌细胞的增殖在心血管疾病的发病机制中起着关键作用。本研究的主要目的是确定莪术（OJS）对肿瘤坏死因子-α（TNF-αα）诱导的人主动脉平滑肌细胞（HASMC）增殖的影响。TNF-α 处理后胸腺嘧啶核苷的掺入增加，而 OJS 处理显著抑制了这种作用。动力学活细胞成像还表明，莪术处理可减少 HASMC 的增殖和迁移。TNF-α 诱导细胞周期调节蛋白的表达，并降低 p21/p27 的表达。然而，OJS 也减弱了 TNF-α 诱导的细胞周期调节蛋白的表达。Western blot 分析结果表明，TNF-α 处理的 HASMC 分泌明胶酶，可能包括 MMP-2/-9，这可能与 HASMC 的侵袭和迁移有关。此外，OJS 以剂量依赖的方式抑制 MMP-2/-9（MMP-2/-9）的 mRNA 表达水平。OJS 抑制 TNF-α 诱导的过氧化氢（HO）的产生和 DCF 敏感的细胞内活性氧（ROS）的形成。此外，OJS 抑制 TNF-α 条件下核因子 κB（NF-κB）的抑制蛋白 kappa B-α（IκB-α）的核易位和磷酸化。我们的结果表明，OJS 对 TNF-α 诱导的 HASMC 增殖和迁移具有抑制作用，表明抑制 MMP-2 和 MMP-9 的表达以及下调 ROS/NF-κB 信号通路的参与。因此，草药汤剂 OJS 可能是抑制包括动脉粥样硬化在内的心血管疾病的一种可能的治疗方法。
