title: α-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen-activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization.
abstract: OBJECTIVE
  To explore whether α-lipoic acid (ALA), a naturally occurring antioxidant, inhibits neointimal hyperplasia by inducing apoptosis of vascular smooth muscle cells and to examine its potential effects on reendothelialization and platelet aggregation.
  
  
  RESULTS
  Restenosis and late stent thrombosis, caused by neointimal hyperplasia and delayed reendothelialization, are significant clinical problems of balloon angioplasty and drug-eluting stents. ALA treatment strongly induced apoptosis of vascular smooth muscle cells and enhanced the expression and cytoplasmic localization of Nur77, which triggers intrinsic apoptotic events. Small interfering RNA-mediated downregulation of Nur77 diminished this proapoptotic effect of ALA. Moreover, ALA increased p38 mitogen-activated protein kinase phosphorylation, and inhibition of p38 mitogen-activated protein kinase completely blocked ALA-induced vascular smooth muscle cell apoptosis and Nur77 induction and cytoplasmic localization. In balloon-injured rat carotid arteries, ALA enhanced Nur77 expression and increased TUNEL-positive apoptotic cells in the neointima, leading to inhibition of neointimal hyperplasia. This preventive effect of ALA was significantly reduced by infection of an adenovirus encoding Nur77 small hairpin (sh)RNA. Furthermore, ALA reduced basal apoptosis of human aortic endothelial cells and accelerated reendothelialization after balloon injury. ALA also suppressed arachidonic acid-induced platelet aggregation.
  
  
  CONCLUSIONS
  ALA could be a promising therapeutic agent to prevent restenosis and late stent thrombosis after angioplasty and drug-eluting stent implantation.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduk-2Ga, Jung-Gu, Daegu 700-721, Korea.
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Do
authors.forename: Sun-Yee
authors.initials: SY
authors.lastname: Kim
authors.forename: Taeg-Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D008063:Thioctic Acid; D048051:p38 Mitogen-Activated Protein Kinases