The effect of tyrphostin AG-556 on intimal thickening in a mouse model of arterial injury.
BACKGROUND
Inflammation has been shown to play an important role in promoting the response to arterial injury and proinflammatory cytokines, such as tumor necrosis factor (TNF) alpha, are candidate mediators. AG-556 is a tyrosine kinase inhibitor proven to be effective in a model of multiple sclerosis-like syndrome in mice due to its immunomodulating effect. In the current study, we investigated the effect of the tyrphostin AG-556 on neointimal thickening and cytokine profile in a model of arterial injury in the mouse.


METHODS
Injury was induced by external cuff placement on the left femoral artery of wild-type C57BL/6 mice. AG-556 dissolved in DMSO was injected intraperitoneally daily to the injured mice in a dosage of 2 mg/mouse. Control mice received DMSO injections. Histological analysis was carried out to assess neointimal formation. Splenocytes were cultured in the absence and presence of a mitogen for evaluation of thymidine incorporation and cytokine production.


RESULTS
AG-556 treatment significantly attenuated intimal thickening (43,000+/-17,000 microm2; n=11) when compared to DMSO administration (286,000+/-127,000 microm2; n=10; P<0.05). Basal interferon-gamma production by splenocytes from AG-556-treated mice was increased by approximately 20-fold in comparison with levels in DMSO-treated animals, whereas Con-A induced secretion of the cytokine was similar between both groups. Levels of TNF-alpha, IL-4 and IL-10 in the culture supernatant from treated and non-treated animals did not differ significantly.


CONCLUSIONS
The tyrosine kinase inhibitor AG-556 may have a role in the reduction of intimal thickening. The effect could be mediated via an immune modulating effect involving a significant increase in the smooth muscle cell inhibitory cytokine IFN-gamma.
George
Jacob
J
Department of Cardiology, Tel-Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, 6 Weizman Street, Tel Aviv University, Israel. jacobg@post.tau.ac.il
Barshack
Iris
I
Keren
Pnina
P
Gazit
Aviv
A
Levitzki
Alexander
A
Keren
Gad
G
Roth
Arie
A
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology*; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology*
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C098981:AG 556; D007371:Interferon-gamma