Abstract 299: Cardiac Fibroblast-derived FGF21 is a Novel Therapeutic Target for Cardiac Pathological Remodeling

Abstract

Background: Fibroblast Growth factor 21(FGF21) is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions. It has been shown that FGF21 has an anti-hypertrophic action for cardiac hypertrophy. We previously reported that murine cardiac FGF21 expression was upregulated by pressure-overload. The objective of this study was to clarify the role of cardiac fibroblast-derived FGF21 in cardiac pathological remodeling. Methods and Results: We generated fibroblast-specific/tamoxifen-inducible FGF21 knockout mice crossing by FGF21flox mice and Col1a2-CreERT mice (FB-FGF21KO). FGF21flox control mice and KO mice were induced cardiac hypertrophy by transverse aortic constriction (TAC). After 3-weeks TAC surgery, we evaluated the cardiac function by echocardiography or conductance catheter. TAC-mediated cardiac hypertrophy or impairment of systolic function were exacerbated in FB-FGF21KO mice. Conductance catheter showed that Tau, diastolic relaxation marker, was exacerbated in FB-FGF21KO mice with TAC. FB-FGF21KO heart with TAC showed significant upregulation in profibrotic genes and down-regulation in Ca2+ ATPase in comparison with control TAC heart. Cardiac Sirt1, which plays a central role in energy metabolism or oxidative stress, increased by TAC was significantly attenuated in FB-FGF21KO heart. Conclusion: Deletion of FGF21 in cardiac fibroblasts exacerbates cardiac dysfunction in response to pressure overload suggesting that cardiac fibroblasts regulates pathological remodeling via FGF21 regulation.