Phospholipase Cɛ Regulation of Cardiac Fibroblasts

Abstract

Heart disease is one of the leading causes of death in the United States. Cardiac fibrosis is commonly associated with heart diseases, such as cardiac hypertrophy and myocardial infarctions. This is characterized as an excess deposition of extracellular matrix that results in a stiffening of the heart. Cardiac fibrosis can lead to arrhythmias, decreased diastolic function and eventually heart failure. Upon injury to the heart, cardiac fibroblasts transition to an activated myofibroblast state, characterized by the expression of α‐smooth muscle actin (αSMA). While the activation of fibroblasts is initially beneficial to the heart, chronic activation of fibroblasts leads to excessive deposition of collagen resulting in the development of fibrosis. Phospholipase Cɛ (PLCɛ) is an important signaling enzyme that is activated by small GTPases downstream of G‐protein coupled receptors (GPCRs) and receptor tyrosine kinases and is important in the cardiac myocyte for the development of cardiac hypertrophy. In this study we sought to elucidate the role of PLCɛ in the transition of cardiac fibroblasts to activated myofibroblasts. Using neonatal rat cardiac fibroblasts, we demonstrate that PLCɛ is highly expressed in fibroblasts compared to myocytes at the mRNA and protein level. Adenovirus encoding for a PLCɛ‐shRNA was used to knockdown PLCɛ in fibroblasts and the ability of the cells to transition to a myofibroblast was examined. Knocking down PLCɛ decreases the mRNA expression of pro‐fibrotic genes such as αSMA, collagen 1, and TGFβ indicating that PLCɛ can regulate pro‐fibrotic gene expression in cardiac fibroblasts. The transition to myofibroblasts induced by transforming growth factor‐β (TGFβ) is reduced in cells treated with PLCɛ‐shRNA compared to cells treated with a control shRNA as assessed by staining of αSMA. In addition, knocking down PLCɛ reduces the ability of the cardiac fibroblasts to respond to pro‐fibrotic Gq‐coupled GPCRs such as the angiotensin receptor and the protease‐activated receptor 1. These data indicate that PLCɛ has an important role in pro‐fibrotic signaling in cardiac fibroblasts and can regulate the myofibroblast transition. Future studies will focus on elucidating the molecular mechanism by which PLCɛ is involved in the pro‐fibrotic signaling response.Support or Funding InformationThis project is supported by grant number T32‐HL007853 from the NIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.