FNDC5 Attenuates Atherosclerotic Plaque Formation and Regulates PPARa/HO-1 in ApoE-/- Mice

Introduction: This study attempted to observe the role of fibronectin type III domain-containing protein 5 (FNDC5) in atherosclerosis development and the underlying mechanism. Methods: After being fed a high-fat diet (HFD), ApoE(-/-) mice were injected with saline, control adenovirus (Ad-vector), or FNDC5 overexpressing adenovirus (Ad-FNDC5). ApoE(-/-) mice fed with a chow diet were considered the control. After 12 weeks of treatment, the levels of serum high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and irisin were detected by commercial kits. Results: Compared with the control, the serum TG, TC, and LDL-C levels, aortic plaque area, and weight were significantly increased, while serum HDL-C and irisin levels were reduced in HFD mice. Treating with Ad-FNDC5 could alleviate these changes in HFD mice and cause the activation of PPARa/HO-1 signaling in aortic tissue. After co-treating with GW6471, a PPARa antagonist, the effects of Ad-FNDC5 on the weight, serum LDL-C, TC, TG, and HDL-C levels, and aortic plaque of HFD mice were partly blocked. Conclusion: Elevated FNDC5 has a delaying effect on atherosclerotic plaque formation, which may be related to the upregulation of PPARa/HO-1 signaling.