Cholesterol trafficking in cardiovascular diseases – TRAFIC

Intracellular cholesterol trafficking is essential for the maintenance of vascular integrity. However, the mechanisms by which cholesterol is transported into the cell are poorly understood. Recently, we showed that a ligand of Wnt signaling, Wnt5a, inhibits intracellular cholesterol accumulation in vascular smooth muscle cells (VSMCs). We show that Wnt5a interacts with lysosomal Niemann-Pick C1/C2 proteins and cholesterol, facilitates its export from the lysosome and protects against atherosclerosis. We also generated antibodies that activate Wnt signaling. We show that these antibodies decrease cholesterol accumulation in VSMCs. The aim of the present project is 1) to study the physiological mechanisms by which Wnt5a facilitates intracellular cholesterol trafficking and interacts with NPCs, 2) to test the therapeutic potential in atherosclerosis of the antibodies we generated and that activate Wnt signaling. 3) In a pilot study, we assayed several Wnt ligands in the sera of 86 patients with familial hypercholesterolemia (FH) and 32 controls. Our results show a marked and significant negative correlation of several of these ligands with the presence of coronary lesions, suggesting that they can be used as biomarkers during atherosclerosis. In a larger study, these markers will be evaluated by Elisa in sera of HF patients from the Rhu Chopin (CHOlesterol Personalized Innovation) registry. This national registry aims to identify new markers of cardiovascular risk. In addition, by sequencing our candidate Wnt genes in FH probands without mutations in the LDLR/APOB/PCSK9/APOE genes, a genetic study will establish the spectrum of variants of these Wnt genes in these patients.