Anti-proliferative and anti-inflammatory effects of topical MAPK inhibition in arterialized vein grafts.
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.
Pintucci
Giuseppe
G
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
Saunders
Paul C
PC
Gulkarov
Iosif
I
Sharony
Ram
R
Kadian-Dodov
Daniella L
DL
Bohmann
Katja
K
Baumann
F Gregory
FG
Galloway
Aubrey C
AC
Mignatti
Paolo
P
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*
D000893:Anti-Inflammatory Agents; D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases