Premium
Anti‐proliferative and anti‐inflammatory effects of topical MAPK inhibition in arterialized vein grafts
Author(s) -
Pintucci Giuseppe,
Saunders Paul C.,
Gulkarov Iosif,
Sharony Ram,
KadianDodov Daniella L.,
Bohmann Katja,
Baumann F. Gregory,
Galloway Aubrey C.,
Mignatti Paolo
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4114fje
Subject(s) - neointima , mapk/erk pathway , medicine , intimal hyperplasia , inflammation , cancer research , kinase , surgery , immunology , microbiology and biotechnology , restenosis , biology , smooth muscle , stent
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 mitogenactivated 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 arterializationinduced 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.