Expression of the FAST-1 transcription factor in coronary artery transplant vasculopathy and activated vascular smooth muscle cells

Background: The activation of vascular smooth muscle cells (VSMCs) causes most of the obliterative vasculopathy responsible for solid-organ allograft failure. Identification of genes expressed in activated VSMCs may provide clues to the pathogenesis and progression of cardiac allograft vasculopathy (CAV). Methods: We performed cDNA micro-array analysis of mRNA isolated from a healthy human coronary artery, from a coronary artery from a patient with CAV, and from quiescent and stimulated cultured human coronary artery VSMCs. Western blot analysis and immunohistochemistry verified fork-head activin signal transdurcer 1 (FAST-1) expression. Results: Fold-change analysis determined that increased expression of a transcription factor involved in transforming growth factor beta (TGF-β) signaling, FAST-1, was induced in arteries with CAV and in activated VSMCs, compared with normal and unstimulated cells. Western blotting confirmed increased FAST-1 expression in arteries with CAV vs normal arteries and arteries from failing hearts and confirmed increased expression in cultured VSMCs stimulated with a variety of cytokines. Immunohistochemical analysis determined that FAST-1 expression localized to neo-intimal VSMCs in rejecting arteries. In cultured VSMCs, FAST-1 immunolocalizes to the nucleus after TGF-β stimulation. Conclusions: These results demonstrate differential expression of the FAST-1 gene in the VSMC response to inflammatory stimuli. Considering the significant role of TGF-β in vascular fibroproliferative diseases, this work suggests that FAST-1 may participate in the VSMC response to injury and may represent a potential molecular target for modulating the progression of CAV.