title: The ADP antagonist MRS2179 regulates the phenotype of smooth muscle cells to limit intimal hyperplasia.
abstract: OBJECTIVE
  ADP plays an important part in platelet aggregation by activating P2Y1 and P2Y12 receptors. The ADP antagonist MRS2179 has been used in thrombosis-related treatments but its effects on vein graft (VG) remodeling is undefined. We examined the effect of MRS2179 on VG intimal hyperplasia and explored the mechanism of action.
  
  
  METHODS
  A mouse model of VG transplantation was established. Mice underwent surgery and received MRS2179 by intraperitoneal injection every other day for 3 weeks. VG remodeling was assessed 4-weeks later. Vascular smooth muscle cells (VSMCs) were isolated and treated with MRS2179. The effect of MRS2179 on the proliferation, migration and inflammatory-cytokine expression of VSMCs was also evaluated.
  
  
  RESULTS
  MRS2179 significantly inhibited VSMC proliferation compared with the control group. Significant inhibitory effects of MRS2179 on VSMC migration was observed in two-dimensional and three-dimensional models. The extent of intimal hyperplasia was significantly less in MRS2179 treated mice than in controls. Reduced migration of macrophage was found in MRS2179 treated mice. Expression of the inflammatory cytokines IL-1β and TNF-α was decreased significantly in the MRS2179 treated group. In addition, decreased phosphorylation was found on Akt, Erk1/2 and p38.
  
  
  CONCLUSIONS
  These data demonstrate that MRS2179 inhibits neointima formation in VGs by regulating the proliferation, and migration of VSMCs, macrophage migration, inflammatory-cytokine secretion and related signaling pathway. Our study provides novel insights regarding purinergic signaling in SMCs in vivo. The P2Y1 receptor may serve as a therapeutic target in neointima formation.
authors.affiliation: Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Shixin
authors.initials: S
authors.lastname: Ma
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Leiqing
authors.initials: L
authors.lastname: Sun
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006965:Hyperplasia / Q000517:prevention & control; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000188:drug therapy; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D019737:Transplants; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014682:Vena Cava, Inferior / Q000166:cytology
chemical_list: D053583:Interleukin-1beta; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D058921:Purinergic P2Y Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D000244:Adenosine Diphosphate; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases