Eupatolide Inhibits PDGF‐induced Proliferation and Migration of Aortic Smooth Muscle Cells Through ROS‐dependent Heme Oxygenase‐1 Induction

Abstract

The abnormal proliferation and migration of vascular smooth muscle cell (VSMC) contributes importantly to the pathogenesis of atherosclerosis and restenosis. Here, we investigated the effects of eupatolide (EuTL), a sesquiterpene lactone isolated from the medicinal plant Inula britannica, on platelet-derived growth factor (PDGF)-induced proliferation and migration of primary rat aortic smooth muscle cells (RASMCs), as well as its underlying mechanisms. EuTL remarkably inhibited PDGF-induced proliferation and migration of RASMCs. Treatment of RASMCs with EuTL induced both protein and mRNA expression of heme oxygenase-1 (HO-1). SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor) and LY294002 (a PI3K inhibitor) did not suppress EuTL-induced HO-1 expression; however, N-acetylcysteine (NAC, an antioxidant) blocked EuTL-induced HO-1 expression. Moreover, treatment of RASMCs with EuTL increased reactive oxygen species (ROS) accumulation and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2); however, this translocation was also inhibited by NAC. NAC or inhibition of HO-1 significantly attenuated the inhibitory effects of EuTL on PDGF-induced proliferation and migration of RASMCs. Taken together, these findings suggest that EuTL could suppress PDGF-induced proliferation and migration of VSMCs through HO-1 induction via ROS-Nrf2 pathway and may be a potential HO-1 inducer for preventing or treating vascular diseases.

Saponins fromAralia taibaiensisAttenuate D-Galactose-Induced Aging in Rats by Activating FOXO3a and Nrf2 Pathways

“…It should be noted that, normally, Nrf2 binds to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, and oxidative stress may modify the cysteines of Keap1 leading to nuclear translocation of Nrf2 and subsequent induction of target gene expressions [48, 49]. The induction of Nrf2 translocation by ROS is reported by different studies [50–52]. However, in the present study, D-galactose-induced oxidative stress decreased Nrf2 translocation and its targeted antioxidants expression.…”

Z‐Ligustilide inhibits benzo(a)pyrene‐induced CYP1A1 upregulation in cultured human keratinocytes via ROS‐dependent Nrf2 activation

“…At the moderate level, ROS may act as upstream mediators of relevant signalling pathways and mediate host defense mechanism. It is known that several compounds exert their protective roles via ROS signalling . However, a massive production of ROS changes the redox signalling function into a deleterious role.…”

Protective effects of the polyphenols (+)-episesamin and sesamin against PDGF-BB-induced activation of vascular smooth muscle cells are mediated by induction of haem oxygenase-1 and inhibition of mitogenic signalling

“…This includes enhanced proliferation and migration of VSMC to the intima due to the exposure to proinflammatory cytokines and growth factors which are released by VSMC and macrophages (Hansson, 2005;Kher & Marsh, 2004;Swirski et al, 2009;Wen, Han, Zheng, & Yang, 2002). Besides tumour necrosis factor (TNF)-alpha Jiang, Jiang, Zhu, Zhang, & Zhan, 2013), PDGF-BB is a potent mitogenic or migratory stimulus for VSMCs and induces the generation of oxidative stress by reactive oxygen species (ROS) (Kim, Hwangbo, Lee, & Lee, 2013;Yamasaki et al, 2001;Yi et al, 2012). PDGF-BB also induces autophagy in VSMC which affects the transition from a contractile to a synthetic phenotype favouring VSMC survival under conditions of elevated ROS levels (Salabei et al, 2013), a characteristic feature during atherosclerosis (West, Guzik, Black, & Channon, 2001;Yokoyama, Inoue, & Kawashima, 2000).…”