Gene transfer of COX-1 improves lumen size and blood flow in carotid bypass grafts.
BACKGROUND
In autologous saphenous vein grafts, prostacyclin (PGI(1)), a vasoprotective molecule produced by normal endothelial cells, is down-regulated compared with ungrafted saphenous veins and normal carotid arteries. Reduced PGI(2) synthesis may contribute to local platelet deposition, vascular smooth muscle cell (VSMC) accumulation, atherosclerosis, and ultimately failure of venous bypass grafts. We have examined whether gene transfer-mediated overexpression of COX-1 in grafted veins (1) increases PGI(2) and cyclic AMP (cAMP) production, (2) leads to vasodilation and improved local blood flow in the presence of hypercholesterolemia, and (3) reduces neointima formation.


METHODS
Jugular veins from New Zealand-White rabbits were incubated for 30 min ex vivo with 1 x 10(10) PFU/mL of an adenoviral vector encoding COX-1 (AdCOX-1; n = 10) or empty control (n = 10) and grafted to the carotid arteries. The rabbits were placed on a high-cholesterol diet for 4 w, and blood flow and histomorphometry of the grafts were assessed.


RESULTS
In the AdCOX-1 group, blood flow was significantly increased (16.0 +/- 3.3 versus 12.5 +/- 3.3 mL/min; P < 0.05) compared with controls, and luminal area (8.9 +/- 1.4 versus 5.3 +/- 1.2 mm(2); P < 0.01) and outer circumference were larger. In six identically treated rabbits, graft PGI(2) and cAMP synthesis was increased at 72 h in AdCOX-1 compared with controls.


CONCLUSIONS
Our data suggest a 30-min ex vivo exposure of vein grafts to AdCOX-1 increased local synthesis of PGI(2) and cAMP after graft surgery and resulted in better graft lumen and blood flow at 4 w.
Eichstaedt
Harald C
HC
Wafic Said Molecular Cardiology and Gene Therapy Research Laboratory, Texas Heart Institute at St Luke's Episcopal Hospital, Houston, Texas, USA.
Liu
Qi
Q
Chen
Zhiqiang
Z
Bobustuc
George C
GC
Terry
Toya
T
Willerson
James T
JT
Zoldhelyi
Pierre
P
D000818:Animals; D002784:Cholesterol / Q000097:blood; D000242:Cyclic AMP / Q000096:biosynthesis*; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D015316:Genetic Therapy; D006937:Hypercholesterolemia / Q000503:physiopathology; D007601:Jugular Veins / Q000378:metabolism / Q000503:physiopathology / Q000637:transplantation*; D011817:Rabbits; D012039:Regional Blood Flow; D014664:Vasodilation
D002784:Cholesterol; D011464:Epoprostenol; D000242:Cyclic AMP; D051545:Cyclooxygenase 1