WISP1 alleviates lipid deposition in macrophages via the PPARγ/CD36 pathway in the plaque formation of atherosclerosis

Lipid deposition in macrophages plays an important role in atherosclerosis. The WNT1‐inducible signalling pathway protein 1(WISP1) can promote proliferation and migration of smooth muscle cells. Its expression is up‐regulated in obesity, which is associated with atherosclerosis, but the effect of WISP1 on atherosclerosis remains unclear. Thus, the objective of our study was to elucidate the role of WISP and its mechanism of action in atherosclerosis via in vivo and in vitro experiments. In our experiment, ApoE‐/‐ mice were divided into 5 groups: control, high‐fat diet (HFD), null lentivirus (HFD + NC), lentivirus WISP1 (HFD + IvWISP1) and WISP1‐shRNA (HFD + shWISP1). Oil Red O staining, immunofluorescence and immunohistochemistry of the aortic sinuses were conducted. Macrophages (RAW264.7 cell lines and peritoneal macrophages) were stimulated with 50 μg/mL oxidized low‐density lipoprotein (ox‐LDL); then, the reactive oxygen species (ROS) level was measured. Oil Red O staining and Dil‐ox‐LDL (ox‐LDL with Dil dye) uptake measurements were used to test lipid deposition of peritoneal macrophages. WISP1, CD36, SR‐A and PPARγ expression levels were measured via Western blotting and ELISA. The results showed that HFD mice had increased WISP1, CD36 and SR‐A levels. The plaque lesion area increased when WISP1 was down‐regulated, and lipid uptake and foam cell formation were inhibited when WISP1 was up‐regulated. Treatment of RAW264.7 cell lines with ox‐LDL increased WISP1 expression via activation of the Wnt5a/β‐catenin pathway, whereas ROS inhibition reduced WISP1 expression. Moreover, WISP1 down‐regulated CD36 and SR‐A expression, and Oil Red O staining and Dil‐ox‐LDL uptake measurement showed that WISP1 down‐regulated lipid deposition in macrophages. These results clearly demonstrate that WISP1 is activated by ox‐LDL at high ROS levels and can alleviate lipid deposition in atherosclerosis through the PPARγ/CD36 pathway.