title: Protective effect of nectandrin B, a potent AMPK activator on neointima formation: inhibition of Pin1 expression through AMPK activation.
abstract: OBJECTIVE
  Neointima is considered a critical event in the development of vascular occlusive disease. Nectandrin B from nutmeg functions as a potent AMP-activated protein kinase (AMPK) activators. The present study addressed whether nectandrin B inhibits intimal hyperplasia in guide wire-injured arteries and examined its molecular mechanism.
  
  
  METHODS
  Neointima was induced by guide wire injury in mouse femoral arteries. Cell proliferation and mechanism studies were performed in rat vascular smooth muscle cells (VSMC) culture model.
  
  
  RESULTS
  Nectandrin B increased AMPK activity in VSMC. Nectandrin B inhibited the cell proliferation induced by PDGF and DNA synthesis. Moreover, treatment of nectandrin B suppressed neointima formation in femoral artery after guide wire injury. We have recently shown that Pin1 plays a critical role in VSMC proliferation and neointima formation. Nectandrin B potently blocked PDGF-induced Pin1 and cyclin D1 expression and nectandrin B's anti-proliferation effect was diminished in Pin1 overexpressed VSMC. PDGF-induced phosphorylation of ERK and Akt was marginally affected by nectandrin B. However, nectandrin B increased the levels of p53 and its downstream target p21 and, also reversibly decreased the expression of E2F1 and phosphorylated Rb in PDGF-treated VSMC. AMPK inhibition by dominant mutant form of adenovirus rescued nectandrin B-mediated down-regulation of Pin1 and E2F1.
  
  
  CONCLUSIONS
  Nectandrin B inhibited VSMC proliferation and neointima formation via inhibition of E2F1-dependent Pin1 gene transcription, which is mediated through the activation of an AMPK/p53-triggered pathway.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, South Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.forename: Jung-Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Tran Thi
authors.initials: TT
authors.lastname: Hien
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Im
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.forename: Moo Yeol
authors.initials: MY
authors.lastname: Lee
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Ji
authors.forename: Yoon Gyoon
authors.initials: YG
authors.lastname: Kim
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D058426:Neointima / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D057772:Vascular System Injuries / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D017705:Lignans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020011:Protective Agents; C524653:nectandrin-B; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse