Fenofibrate represses matrix metalloproteinase-2 in endothelial cells

Fenofibrate is a widely used to ameliorate hyperlipidemia and/or hypercholesterolemia in patients at risk of cardiovascular disease. To date, most of its favorable effects have been attributed to its activation of peroxisome proliferator activated receptor alpha (PPARα), which alters lipid metabolism, contributing to an improved lipid profile. Lines of evidence suggest pleotrophic effects of fenofibrate in cardiovascular system. Given that endothelium is the frontier of vasculature and its dysfunction is prelude of various vascular disorders, e.g. atherosclerosis and arterial stiffening, we investigated the effect of fenofibrate in human endothelial cell (EC) line (Eahy926). Fenofibrate treatment in ECs repressed matrix metalloproteinase-2 (MMP-2) expression in ECs as well as endothelial MMP-2 secretion, associated with decreased MMP-2 activity. In parallel, fenofibrate activated endothelial nitric oxide synthase (eNOS), demonstrated by Ser1177 phosphorylation. Inhibition of eNOS by L-NAME attenuated fenofibrate-suppressed MMP-2, indicating fenofibrate inhibits MMP-2 requires eNOS-derived NO. Collectively, these findings suggest that fenofibrate activates eNOS and increases NO-bioavailability, which in turn suppresses overactivation of MMP-2, contributing to maintenance of endothelial homeostasis. The present study provides a molecular rationale in which fenofibrate exerts vascular protective effects, facilitating the clinical application of its derived medicine.