ABSTRACT
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease. It is estimated that 60% of all nontraumatic lower-extremity amputations performed annually in the United States are in patients with diabetes and CLTI. The consequences of this condition are extraordinary, with substantial patient morbidity and mortality and high socioeconomic costs. Strategies that optimize the success of arterial revascularization in this unique patient population can have a substantial public health impact and improve patient outcomes. This article provides an up-to-date comprehensive assessment of management strategies for patients afflicted by both diabetes and CLTI.
ABSTRACT
De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of Cept1 via induced VE-cadherin-CreERT2-mediated recombination (Cept1Lp/LpCre +). Cept1Lp/LpCre + ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre + mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPARα signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribonuclease-prepared siRNA decreased PPARα phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre + mice, Cept1Lp/LpCre + Ppara -/- mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα.
