title: Anti-proliferative and anti-inflammatory effects of topical MAPK inhibition in arterialized vein grafts.
abstract: Vein graft failure following bypass surgery is a frequent and important clinical problem. The vascular injury caused by arterialization is responsible for vein graft intimal hyperplasia, a lesion generated by medial smooth muscle cell proliferation and migration into the intima, increased extracellular matrix deposition, and formation of a thick neointima. Development of the neointima into a typical atherosclerotic lesion and consequent stenosis ultimately result in vein graft failure. Endothelial damage, inflammation, and intracellular signaling through mitogen-activated protein kinases (MAPKs) have been implicated in the early stages of this process. We therefore investigated the effects of topical inhibition of ERK-1/2 MAPK activation on vascular cell proliferation and apoptosis, and on the inflammatory response in a canine model of vein graft arterialization. For this purpose, vein grafts were incubated with the MEK-1/2 inhibitor, UO126, ex vivo for 30 min before grafting. This treatment effectively abolished arterialization-induced ERK-1/2 activation, decreased medial cell proliferation, and increased apoptosis. UO126 treatment also inhibited the vein graft infiltration by myeloperoxidase-positive inflammatory cells that follows vein graft arterialization. Thus, topical ex vivo administration of MAPK inhibitors can provide a pharmacological tool to prevent or reduce the vascular cell responses that lead to vein graft intimal hyperplasia and graft failure.
authors.affiliation: The Seymour Cohn Cardiovascular Surgical Research Laboratory, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016, USA. pintug01@med.nyu.edu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pintucci
authors.forename: Paul C
authors.initials: PC
authors.lastname: Saunders
authors.forename: Iosif
authors.initials: I
authors.lastname: Gulkarov
authors.forename: Ram
authors.initials: R
authors.lastname: Sharony
authors.forename: Daniella L
authors.initials: DL
authors.lastname: Kadian-Dodov
authors.forename: Katja
authors.initials: K
authors.lastname: Bohmann
authors.forename: F Gregory
authors.initials: FG
authors.lastname: Baumann
authors.forename: Aubrey C
authors.initials: AC
authors.lastname: Galloway
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology*; D002339:Carotid Arteries / Q000601:surgery*; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D007249:Inflammation / Q000188:drug therapy*; D007601:Jugular Veins / Q000637:transplantation*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023421:Models, Animal; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases