Abstract 283: Fenofibrate Induces Endothelial Cell Tubule Formation Independent of Phospholipogenesis

Fenofibrate, a proliferator-activated receptor (PPAR)α agonist, is the only oral medication demonstrated to prevent lower extremity amputations in diabetic patients. Phosphatidylcholines, generated by choline-ethanolamine phosphotransferase 1 (CEPT1) via the Kennedy Pathway, also induce PPARα activation, but their metabolism is altered in the setting of diabetes. It is unknown whether CEPT1 is essential for fenofibrate-mediated endothelial cell (EC) function. To evaluate this, we generated a murine model for conditional knockdown of Cept1 in the endothelium ( Cept1EC KO). Heart ECs (MHECs) were harvested from 6wk old Cept1EC KO and wildtype (WT) littermates, and cultured in vitro on growth factor-reduced Matrigel. Cultures were then supplemented with VEGF (50ng/mL), bFGF (50ng/mL), and fenofibrate (25uM), then assessed longitudinally at 0, 4, and 6 hours. We observed that compared to WT, Cept1EC KO MHECs had significantly less tubule formation (p < 0.0001). VEGF and bFGF failed to rescue Cept1EC KO MHECs, but demonstrated a robust agonist response in WT MHECs (bFGF: p=0.003; VEGF: p=0.0002). Interestingly, fenofibrate demonstrated complete rescue of Cept1EC KO MHECs at 4 and 6 hours of culture. This finding demonstrates that fenofibrate restores EC function even in the setting of impaired phospholipid biosynthesis. This observation may partially explain how fenofibrate confers added benefits in subjects with diabetic and peripheral arterial disease. Future work will further elucidate this mechanism of action in diabetic subjects.