Abstract 17336: A Hepato-Cardiac FGF21 Signaling Axis Promotes Cardiac Hypertrophy

Abstract

FGF21 is expressed mainly in the liver and other organs, including the heart. The role of FGF21 is controversial, with potential benefits for obesity and certain heart conditions, but also associations with heart failure and increased mortality. We found higher serum FGF21 levels (2.5-fold) in left ventricular hypertrophy patients (N=31) compared to those without hypertrophy (N=45). Similarly, mice subjected to Transverse Aortic Constriction (TAC) had elevated plasma FGF21 levels and hepatic expression. Surprisingly, a time course experiment showed that liver FGF21 production peaked 3 days post-TAC (prior to the onset of hypertrophy), while an unexpected increase of cardiac FGF21 expression was observed 2 weeks post-TAC, coinciding with hypertrophy and dysfunction. FGF21 expression in skeletal muscle did not change. As in mice, hypertensive individuals (N=6) showed a 14-fold increase in cardiac FGF21 mRNA levels compared to normotensive (N=6). To delineate the role of hepatic and cardiac FGF21 in hypertrophy, TAC was performed on mice with hepatocyte- (HEP-FGF21-KO) or cardiomyocyte-specific (CM-FGF21-KO) FGF21 ablation. Both HEP-FGF21-KO and CM-FGF21-KO mice were protected from hypertrophy, pro-hypertrophic signaling, fibrosis, and cardiac dysfunction. Notably, hepatocyte FGF21 deletion prevented cardiac FGF21 upregulation with TAC, suggesting control of CM FGF21 expression by liver-derived FGF21 and highlighting the role of CM FGF21 in driving cardiac hypertrophy. This was confirmed by treatment of AC16 human cardiomyocytes with recombinant FGF21 that increased endogenous FGF21 expression and cell size. RNAseq analysis revealed attenuation of cardiac fibrosis- and hypertrophy-related transcriptome in both HEP-FGF21-KO and CM-FGF21-KO mice. To explore if FGF21 increase is a cause and not a consequence of cardiac hypertrophy, we developed anti-sense oligonucleotides against FGF21 and administered them in C57BL/6 mice with TAC. ASO-FGF21 treatment attenuated cardiac hypertrophy and fibrosis and improved cardiac function. Thus, FGF21 emerges as a therapeutic target for pathological cardiac hypertrophy.