Everolimus attenuates neointimal hyperplasia in cultured human saphenous vein grafts.
OBJECTIVE
Neointimal hyperplasia is the first step in a cascade leading to a reduced patency rate of saphenous vein grafts in comparison to arterial grafts in coronary artery bypass grafting. Using cultured human saphenous vein grafts as a model for coronary artery bypass grafting, we investigated if the mammalian target of rapamycin inhibitor everolimus attenuates neointimal hyperplasia.


METHODS
Saphenous vein grafts from 10 patients undergoing coronary artery bypass grafting were processed as follows: from each patient, one segment served as baseline control at day 0. Two segments were cultured in a neointimal hyperplasia model separately. One received no treatment and the other everolimus (1 microM). All vein grafts underwent histomorphometric analysis, assessment of proliferation by Ki-67 immunostaining and quantification of phospho-S6 ribosomal protein using western blot analysis.


RESULTS
Everolimus treatment resulted in reduced neointimal hyperplasia (thickness 3.7+/-1.2 microm) compared to untreated controls (10.1+/-2.5 microm, p=0.008). The intima/intima+media-ratio was reduced in the everolimus group (0.10+/-0.02) compared to untreated controls (0.24+/-0.07, p=0.008). The number of Ki-67 positive proliferating cells in everolimus treated vein grafts (15+/-7 cells/high power field) showed a tendency of reduction compared to untreated controls (36+/-20 cells/high power field, p=0.036). Finally, everolimus treatment resulted in downregulation of S6 ribosomal protein phosphorylation in comparison to untreated controls.


CONCLUSIONS
Everolimus is able to reduce neointimal proliferation in cultured human saphenous vein grafts by inhibition of the mammalian target of rapamycin, even though different transfection methods are to be evaluated for a clinical application in coronary artery bypass grafting.
Semsroth
Severin
S
Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria. severin.semsroth@i-med.ac.at
Stigler
Robert G
RG
Bernecker
Oliver Y
OY
Ruttmann-Ulmer
Elfriede
E
Troppmair
Jakob
J
Macfelda
Karin
K
Bonatti
Johannes O
JO
Laufer
Guenther
G
D015153:Blotting, Western; D001026:Coronary Artery Bypass / Q000379:methods*; D000068338:Everolimus; D006801:Humans; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis; D009924:Organ Culture Techniques; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014654:Vascular Patency / Q000187:drug effects
D007166:Immunosuppressive Agents; D019394:Ki-67 Antigen; D000068338:Everolimus; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus