title: 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.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 200-701, Republic of Korea.
authors.forename: Namho
authors.initials: N
authors.lastname: Kim
authors.forename: Cheol
authors.initials: C
authors.lastname: Hwangbo
authors.forename: Suhyun
authors.initials: S
authors.lastname: Lee
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D038143:Inula / Q000737:chemistry; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C113580:U 0126; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C001200:eupatolide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C093642:SB 203580; D000111:Acetylcysteine
keywords: eupatolide; heme oxygenase-1; migration; proliferation; vascular smooth muscle cell