Inhibition of intimal thickening in the rat carotid artery injury model by a nontoxic Ras inhibitor.
BACKGROUND
Neointimal formation with and without previous vascular injury is common after balloon dilation and in transplant arteriosclerosis. It involves proliferation and migration of medial smooth muscle cells and inflammation, processes that are regulated by Ras proteins and their down-stream effectors. Farnesylthiosalicylate (FTS) is a Ras inhibitor that interferes with Ras membrane anchorage and affects Ras proteins in their active state. In the present study, we tested the hypothesis that systemic administration of FTS will suppress intimal thickening in the rat carotid injury model.


RESULTS
The effects of FTS on rat vascular smooth muscle cells (VSMC) and splenocytes proliferation were evaluated in vitro. The in vivo effects of FTS on the neointima of balloon-injured male Wistar rats, treated daily for 2 weeks with FTS (5 mg/kg weight, intraperitoneally) were evaluated by determination of Ras, Ras-GTP, and active ERK levels (3 days after injury), and by quantitative determination of the extent of intimal thickening and immunohistochemistry for Ras, iNOS, NFkB, and Ki-67 (2 weeks after injury). FTS inhibited VSMC and splenocyte proliferation as well as interferon-gamma secretion by splenocytes in a dose-dependent manner. Compared with controls, FTS treatment resulted in a strong decrease in Ras-GTP and active ERK, and it significantly reduced intimal thickening after the injury. Ras expression appeared predominantly at areas of neointima regardless of the treatment group. NFkB and iNOS-positive cell numbers were reduced in sections of FTS treated rats.


CONCLUSIONS
FTS appears to act as a potent inhibitor of intimal thickening in a model of experimental arterial injury.
George
Jacob
J
Department of Cardiology and the Cardiovascular Research Laboratory,Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Israel. jacobg@post.tau.ac.il
Sack
Jessica
J
Barshack
Iris
I
Keren
Pnina
P
Goldberg
Iris
I
Haklai
Roni
R
Elad-Sfadia
Galit
G
Kloog
Yoel
Y
Keren
Gad
G
D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D018631:ras Proteins