FGF21 Overexpression Protects against Atherosclerotic Calcification by Suppressing Endothelial Activation and Endothelial-Mesenchymal Transition

Abstract

Background: Vascular calcification (VC) is associated with high rates of morbidity and mortality. It can complicate efforts to safely and effectively complete percutaneous interventions and surgical procedures. While fibroblast growth factor 21 (FGF21) has been identified as a potential therapeutic candidate for non-alcoholic steatohepatitis and type 2 diabetes, whether it exerts beneficial cardiovascular effects by modulating atherosclerosis-associated VC remains to be determined. Methods: FGF21 therapeutic benefits were evaluated using an AAV (adeno-associated virus)-based approach to overexpress this protein in an atherosclerotic model system consisting of ApoE^-/- (Apolipoprotein E) mice fed with a Western diet. Results: The persistent FGF21 overexpression resulted in reductions in murine body weight and a concomitant improvement in the lipid profiles of mice. VC rates were significantly reduced in response to FGF21 overexpression without affecting the function of other major organs. Mechanistically, FGF21 protective effects were found to be mediated by the suppression of endothelial activation and the endothelialmesenchymal transition (EndMT) as confirmed in an in vitro ox-LDL (oxidized low-density lipoprotein)-treated mouse aortic endothelial cell model system. Conclusions: Together, these data suggest that FGF21 therapeutic benefits as an inhibitor of atherosclerotic calcification may be related to its ability to inhibit endothelial activation and EndMT induction.