title: Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts.
abstract: BACKGROUND
  Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. Rapamycin coated stents have been demonstrated to suppress restenosis in experimental and clinical studies of percutaneous coronary catheter intervention. We investigated whether rapamycin can reduce neointima formation in a mouse model of vein graft disease.
  
  
  METHODS
  C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 100 microg or 200 microg of rapamycin was applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 6 weeks and underwent morphometric analysis as well as immunohistochemical analysis.
  
  
  RESULTS
  In grafted veins without treatment (controls), median intimal thickness was 9.6 (6.4 to 29)microm, 11.9 (7.9 to 39.9)microm, 46.6 (12.4 to 57.7)microm, and 57.5 (32.5 to 71.1)microm after 1, 2, 4, and 6 weeks, respectively. Treatment with 100 microg or 200 microg rapamycin showed a dose dependent reduction of intimal thickness. In the 200 microg rapamycin treatment group the intimal thickness was 4.3 (3.4 to 5.6)microm, 3.8 (3.2 to 6.3)microm, 17.1 (4.8 to 63)microm, and 33.9 (11.3 to 80.3)microm after 1, 2, 4, and 6 weeks, respectively. This difference of intimal thickness of 200 microg treated animals compared with controls was statistically significant at 1 and 2 weeks. Immunohistochemically the reduction of intimal thickness was associated with a decreased amount of infiltration of CD-8 positive cells and a decreased amount of metallothionein positive cells in the rapamycin treated grafts.
  
  
  CONCLUSIONS
  We conclude that perivascular application of rapamycin inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that rapamycin may have a therapeutic potential for the treatment of vein graft disease.
authors.affiliation: Department of Cardiac Surgery, Innsbruck University, Innsbruck, Austria. thomas.schachner@uibk.ac.at
authors.forename: Thomas
authors.initials: T
authors.lastname: Schachner
authors.forename: Yping
authors.initials: Y
authors.lastname: Zou
authors.forename: Alexander
authors.initials: A
authors.lastname: Oberhuber
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Thomas
authors.initials: T
authors.lastname: Mairinger
authors.forename: Günther
authors.initials: G
authors.lastname: Laufer
authors.forename: Johannes O
authors.initials: JO
authors.lastname: Bonatti
mesh_terms: D000818:Animals; D023903:Coronary Restenosis / Q000517:prevention & control; D004195:Disease Models, Animal; D005079:Excipients; D006965:Hyperplasia; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020442:Poloxamer; D020123:Sirolimus / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D005079:Excipients; D007166:Immunosuppressive Agents; D020442:Poloxamer; D020123:Sirolimus