Relationship between TCF21 gene, Smooth Muscle Cells, and Coronary Heart Disease

While treatment of atherosclerotic coronary heart disease (CHD) has focused primarily on risk factors, more fundamental understanding of the atherosclerosis disease process in the vessel wall would promote the development of more specific treatments. TCF21 gene is expressed in progenitor cells of the proepicardial organ (PEO) in the early embryo, and these cells are known to be the source of coronary smooth muscle cells (SMC) in this unique circulatory bed. It has been hypothesized that TCF21 in the PEO supports proliferation and inhibits differentiation of SMC progenitor cells as they migrate over the surface of the heart. Such functions are known to be important for SMC response to injury in the setting of atherosclerosis in the coronary circulation, raising the hypothesis that this gene is important in CHD. SMC play critical and complex roles in vascular disease, but whether the balance of SMC activities primarily promotes or inhibits vascular disease remains an unanswered question. We will manipulate expression of TCF21 to better understand how this gene differentially regulates disease-related cellular processes in SMC. We will increase or decrease TCF21 expression by transfecting a recombinant TCF21 construct or short inhibitory RNA molecules into the human coronary SMC, and measure cellular proliferation as the rate of cell division, differentiation as the expression of SMC-specific markers, and apoptosis as evidenced by caspase-3 activation. We anticipate that alterations in TCF21 expression level will significantly impact cell fate decisions.