The Effect Of Tyrphostin AG-556 A TNF-Alpha Inhibitor, On Intimal Thickening In A Mouse Model Of Arterial

Aharon Frimmerman
Tel Aviv Medical Center, Department of Cardiology

Background: Inflammation has been shown to play a dominant role in promoting the response to arterial injury. The effect is partially mediated by proinflammatory cytokines the prototypic of which is tumor necrosis (TNF) alpha. AG-556 is tyrosine kinase inhibitor proven to be effective in a model of multiple sclerosis like syndrome in mice, due to TNF-alpha inhibition. In the current study we investigated the effect of the tyrphostin AG-556 on intimal formation 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 IP daily to the injured mice in a dosage of 2mg/mouse. Control mice received DMSO injections. At the end of the study arteries were paraffin fixed for evaluation of intimal thickening. Splenocytes were cultured in the absence and presence of a mitogen for evaluation of thymidine incorporation and cytokine production by ELISA.

Results: AG-556 treatment reduced the number of injured arteries exhibiting intimal thickening (4/11) when compared to DMSO administration (8/10; 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 were similar between both groups. Levels of TNF-α, IL-4 and IL-10 in the culture supernatant from treated and non-treated animals did not differ significantly.

Conclusion: The tyrosine kinase inhibitor AG-556 may serve as a novel treatment in the prevention intimal thickening. The effect could be mediated via a significant increase in the smooth muscle cell inhibitory cytokine IFN-γ.