Topical mitogen-activated protein kinases inhibition reduces intimal hyperplasia in arterialized vein grafts.
OBJECTIVE
Vein graft arterialization results in activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases-1 and -2 (ERK1/2), which have been implicated in cell proliferation, migration, and apoptosis. The goal of our study was to characterize the effect of MAPK inhibition on intimal hyperplasia (IH) in arterialized vein grafts in hypercholesterolemic rabbits.


METHODS
Reversed bilateral jugular vein to common carotid artery interposition grafts were constructed in 16 New Zealand White rabbits. The veins were incubated for 30 min prior to grafting with either the synthetic ERK1/2 activation inhibitor UO126 or the control vehicle. Vein graft and control jugular vein were harvested 3 h, 1 d, and 28 d after arterialization for histological and biochemical analyses.


RESULTS
Treatment with UO126 was associated with 31% reduction in mean intimal area (1.68 +/- 0.78 mm(2)versus 2.44 +/- 1.65 mm(2); mean +/- SD; P = 0.036) relative to controls. The intima-to-media ratio of UO126-treated vein grafts decreased by 29% (0.53 +/- 0.04 versus 0.74 +/- 0.06; mean +/- SD; P < 0.01) compared to controls, vehicle-treated vein grafts. There was also significant increase in apoptosis in UO126-treated vein graft medial cell layer at 1 d.


CONCLUSIONS
Topical administration of UO126 before vein grafting significantly decreases IH in arterialized vein grafts in hypercholesterolemic rabbits. These results may have significant implications for the development of strategies aimed at blocking or reducing IH in bypass grafts. Therefore, further evaluation of this simple strategy to improve vein graft patency following coronary artery or peripheral vascular bypass surgery is warranted.
Gulkarov
Iosif
I
The Seymour Cohn Cardiovascular Research Laboratory, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016, USA.
Bohmann
Katja
K
Cinnante
Karma M
KM
Pirelli
Luigi
L
Yu
Pey-Jen
PJ
Grau
Juan B
JB
Pintucci
Giuseppe
G
Galloway
Aubrey C
AC
Mignatti
Paolo
P
D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000637:transplantation*; D017536:Carotid Artery, Common / Q000601:surgery; D002455:Cell Division; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006965:Hyperplasia / Q000517:prevention & control*; D007601:Jugular Veins / Q000601:surgery*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000627:therapeutic use*; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases