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

Abstract

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.