Influence of ischemic injury on vein graft remodeling: role of cyclic adenosine monophosphate second messenger pathway in enhanced vein graft preservation.
OBJECTIVE
Endothelial injury during the harvest of saphenous vein grafts might play an important role in the development of vein graft disease after coronary artery bypass grafting. Using a murine autologous arterialized vein patch model, we tested whether the initial ischemic insult of vein grafts was linked to the later development of graft neointimal hyperplasia and whether the restoration of the cyclic adenosine monophosphate second messenger pathway would attenuate the development of neointimal hyperplasia.


METHODS
A segment of the external jugular vein of a mouse was grafted onto its abdominal aorta. Three weeks after the operation, the degree of neointimal hyperplasia of the implanted graft was compared among (1) grafts without preservation, (2) grafts with 2 hours of preservation (25 degrees C) in heparinized saline, and (3) grafts with 2 hours of preservation in heparinized saline in the presence of a cyclic adenosine monophosphate analog. In addition, cyclic adenosine monophosphate contents of vein grafts and leukocyte adherence to the graft endothelium were assessed.


RESULTS
Cyclic adenosine monophosphate contents were significantly decreased after 2 hours of preservation (212 +/- 8 vs 156 +/- 5 pmol/L, P < .01). The grafts preserved for 2 hours showed greater neointimal hyperplasia compared with the grafts without preservation (neointimal expansion, 68.7% +/- 9.6% vs 46.1% +/- 4.8%; P < .01). The addition of a cyclic adenosine monophosphate analog to the preservation solution significantly suppressed neointimal hyperplasia of grafts preserved for 2 hours (44.3% +/- 5.0%). Inhibiting the cyclic adenosine monophosphate-dependent protein kinase by adding Rp-cAMPS abrogated the beneficial effects. Furthermore, grafts preserved for 2 hours had significantly more leukocytes adhering to the graft endothelium 24 hours after the operation compared with nonpreserved grafts, which was significantly reduced by the cyclic adenosine monophosphate treatment.


CONCLUSIONS
Ischemic insult during vein graft harvest and preservation is a key factor in the development of vein graft neointimal hyperplasia at least in part caused by the depletion of cyclic adenosine monophosphate. We conclude that stimulation of the cyclic adenosine monophosphate second messenger pathway might be a potential strategy for the prevention of vein graft disease.
Sakaguchi
Taichi
T
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Asai
Tomohiro
T
Belov
Dmitri
D
Okada
Morihito
M
Pinsky
David J
DJ
Schmidt
Ann Marie
AM
Naka
Yoshifumi
Y
D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001807:Blood Vessel Prosthesis; D004195:Disease Models, Animal; D006084:Graft Rejection; D006085:Graft Survival; D007601:Jugular Veins / Q000637:transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011309:Preservation, Biological; D012016:Reference Values; D015427:Reperfusion Injury / Q000517:prevention & control*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016378:Tissue Transplantation / Q000009:adverse effects / Q000379:methods; D020858:Tissue and Organ Harvesting; D017539:Tunica Intima / Q000473:pathology*; D014680:Veins / Q000473:pathology* / Q000637:transplantation*
D000249:Adenosine Monophosphate