STAT4 and the proliferation of artery smooth muscle cells in atherosclerosis

Artery smooth muscle cell proliferation is of key importance in the development of atherosclerosis and restenosis following PTCA. In order to understand gene regulation involved in these processes, vascular smooth muscle cells (VSMCs) from atherosclerosis-susceptible White Carneau (WC) and atherosclerosis-resistant Show Racer (SR) pigeons were used to identify transcription factors involved in the enhanced proliferation of WC VSMCs. With protein/DNA array, signal transducer and activator of transcription 4 (STAT4) was found to have over a 10-fold increase in expression in WC compared to SR VSMCs. The difference was confirmed with electrophoretic-mobility shift assay (EMSA) and Western blot. Cells cultured under low serum had 5-fold higher levels of STAT4 in WC compared to SR. By Western analysis, aortic tissue from newly hatched WC pigeons had 1.7-2.0 times greater STAT4 expression than in SR pigeons. A pathway whereby enhanced STAT4 may be associated with enhanced proliferation was identified following IL-12 stimulation of WC VSMCs where 3-fold increases in proliferation and 2-fold higher expression of STAT4 were measured. The findings suggest STAT4 may play a role in VSMC proliferation and describe a unique pigeon model system in which to study STAT4 as a gene target for atherosclerosis therapy.