Abstract 130: Epicardial-to-Myocyte Hypertrophic Signaling is Mediated by Epicardial/Mesenchymal Status and Protein Arginine Methyltransferase-1

Abstract

The epithelial-to-mesenchymal transition (EMT) is an important cellular mechanism in a diverse range of biological processes such as development, wound healing, cancer metastasis, and organ fibrosis. Epicardial cells are mesothelial cells lining the outer surface of the heart that are an important progenitor population and a source of growth factors during development. Epicardial cells undergo EMT and invade the myocardium, differentiating into cardiac fibroblasts and coronary smooth muscle cells. Of note, resident fibroblasts of epicardial origin are a major cellular mediator of cardiac fibrosis. Our recent work has established an important function for the protein arginine methyltransferase PRMT1 in EMT. We hypothesized that PRMT1 is required for EMT in a mouse epicardial cell line (MEC-1). We found that PRMT1 is required for a subset of the EMT marker changes in epicardial EMT, such as upregulation of vimentin, fibronectin, and slug, as well as loss of E-cadherin. Furthermore, PRMT1 knockdown reduced MEC-1 migration and invasion, suggesting that PRMT1 is critical for epicardial progenitor function. Epicardial cells secrete a variety of signaling factors that affect cardiomyocyte proliferation and structure. This is a critical component of heart development, and may also affect heart diseases such as hypertophic heart failure. Therefore we assessed whether EMT and PRMT1 affect the paracrine functions of epicardial cells. Co-culture of MEC-1 cells with rat neonatal cardiomyocytes caused cardiomyocyte hypertrophy, and this was enhanced when MEC-1 cells were pre-treated with TGF-β to induce EMT. Interestingly, MEC-1 cells treated with PRMT1 siRNA also induced cardiomyocyte hypertrophy, but TGF-β pre-treatment of these cells did not enhance this effect. In conclusion, epicardial EMT is largely dependent on PRMT1. Epicardial cells also promote cardiomyocyte hypertrophy, which is enhanced in epicardial cells that have undergone PRMT1-mediated EMT towards a mesenchymal fate. These studies establish a role for protein methylation in the EMT process, and could lead to novel treatments for heart failure and other diseases affected by EMT.