Abstract 228: Activation of the Free Fatty Acid Receptor GPR120 Prevents Fibrosis in NIH3T3 Cells and Primary Cardiac Fibroblasts

Abstract

Fibrosis significantly contributes to contractile dysfunction and pathologic ventricular remodeling in heart failure. Recently, we showed for the first time that ω3-polyunsaturated fatty acids (ω-PUFAs) prevent fibrosis and cardiac dysfunction in pressure-overload induced heart failure through inhibition of collagen expression, fibroblast proliferation, and fibroblast-to-myofibroblast transformation. In cultured cardiac fibroblasts, we found that ω3-PUFAs induced eNOS activity to prevent TGFβ1-Smad2/3 pro-fibrotic signaling. Mechanistically, ω3-PUFAs are thought to regulate ion channels or to incorporate into the membrane and alter the properties of lipid-rafts, but how a fatty acid might activate eNOS is unknown. Recently, GPR40 and GPR120 were identified as receptors for long-chain fatty acids (FFARs). Here, we examined GPR120 regulation of cardiac fibrosis. Among the FFARs, GPR40, 41, 43, 84, and 120, GPR120 mRNA was expressed at highest level in whole heart. Furthermore, we detected GPR120 expression in isolated cardiac myocytes and fibroblasts, as well as NIH3T3 mouse embryonic fibroblasts. To determine if activation of GPR120 was sufficient to prevent fibrosis, we tested the ability of the GPR120 agonist GW9508 to prevent TGFβ1-induced fibrosis in both NIH3T3 cells and primary cultures of cardiac fibroblasts. In both NIH3T3 cells and primary cardiac fibroblasts, TGFβ1 (1 ng/ml) induced a pro-fibrotic response indicated by increased fibroblast proliferation, α-smooth muscle actin expression, and collagen I expression. In both cell types, pre-treatment with GW9508 significantly inhibited TGFβ1-induced proliferation (63% in NIH 3T3 cells and 52% in cardiac fibroblasts, respectively), α-smooth muscle actin expression (78% in NIH 3T3 cells, 90% in cardiac fibroblasts), and collagen I expression. In summary, our results demonstrate for the first time, that GPR120 signaling in the heart prevents fibrosis.