Abstract 11626: A Hepato-Cardiac FGF21 Axis Activates a Cardiac FGF21 Autocrine Mechanism That Causes Hypertrophy With Pressure Overload

Abstract

FGF21 is expressed mainly in the liver and other organs, including skeletal muscle and heart. It exerts its actions by binding to its receptors (FGFR) and the co-receptor β-klotho. Despite evidence about protective action of FGF21 in different animal disease models, elevated plasma FGF21 levels have been reported in patients with heart failure. Thus, it remains unknown whether elevation in human heart failure is part of the disease’s pathophysiology or a protective response. Staining of heart sections from end-stage heart failure patients showed increased FGF21 that correlated with higher plasma FGF21 levels. To assess the relative contribution of cardiac and extracardiac FGF21 in heart failure, we generated 3 animal models with cardiomyocyte- (CM-FGF21-KO), hepatocyte- (Alb-FGF21-KO) or skeletal muscle-specific FGF21 (MLC-FGF21-KO) deletion and subjected them to transverse aortic constriction (TAC) for 3 days, 2, 4, and 8 weeks. Hepatic expression and plasma levels of FGF21 were increased 3 days post-TAC. Cardiac FGF21 expression was also increased after 2 weeks of TAC. Surprisingly, the pro-hypertrophic effect of TAC was abolished in both Alb-FGF21-KO and CM-FGF21-KO mice. Interestingly, cardiac FGF21 expression was not increased in CM-FGF21-KO mice despite the high plasma FGF21 levels. The MLC-FGF21-KO mice were not protected. Thus, cardiomyocyte FGF21 upregulation mediates cardiac hypertrophy in response to pressure overload. To investigate if cardiomyocyte FGF21 expression is controlled by FGF21 that is released from the liver, we treated human AC16 cells with recombinant FGF21, which increased endogenous FGF21 mRNA and protein, pointing to an autoregulatory FGF21-based induction of cardiac FGF21 expression. This auto-regulatory loop was potentiated by increased expression of cardiac FGFR1 in wild-type mice subjected to TAC that was attenuated in CM-FGF21-KO mice. Accordingly, we observed increased pro-hypertrophic cardiac signaling (pAMPK, pERK,Bnp, Tnfα) in wild-type mice with TAC, but not in CM-FGF21 KO mice. Conclusively, a hepato-cardiac FGF21-based signaling axis governs cardiomyocyte FGF21 expression, which accounts for cardiac hypertrophy. Inhibition of either hepatic or cardiomyocyte FGF21 is cardioprotective.