title: SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes.
abstract: Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes.
  
  
  
  We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids.
  
  
  
  Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury.
  
  
  
  Suppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Lockhart
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Center for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
authors.forename: Lars Melholt
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Xuanchun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.affiliation: Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA. George.King@Joslin.harvard.edu.
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D060888:Real-Time Polymerase Chain Reaction; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
chemical_list: D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
keywords: Diabetes; Insulin resistance; Restenosis; SHP-1