SIRT1 mediates the inflammatory response of macrophages and regulates the TIMP3/ADAM17 pathway in atherosclerosis
Dong Jia, Ping Wei, Meng Wang, Dan Wang, Liguo Zhang, Yang Cao
Abstract
Macrophage polarization and the resulting phenotype have versatile roles in atherosclerosis. The study aims to decipher the role of SIRT1 in regulating macrophage phenotypes and atherosclerosis development. Two mouse lines of SIRT1 △Mac /ApoE −/− and SIRT1 fl/fl /ApoE −/− were fed with high-fat diet to generate atherosclerotic lesion. Mouse peritoneal macrophages were isolated and transfected with SIRT1-overexpressing vector or vector-null. The SIRT1 △Mac /ApoE −/− mice exhibited greater atherosclerotic lesions, stronger immunofluorescence staining for M1-like macrophage marker, iNOS, and weaker immunofluorescence staining for M2-like macrophage marker, Arginase-1, than the SIRT1 fl/fl /ApoE −/− littermates. The gene expressions of M1 markers (IL-1β, IL-6, and iNOS) were increased and those of M2 markers (IL-10 and Arg-1) decreased in both aortic roots and peritoneal macrophages from SIRT1 △Mac /ApoE −/− mice, whereas SIRT1 overexpression rectified the changes in M1/M2 expression. A declined expression of TIMP3 with an increased expression of ADAM17 was noted in SIRT1 △Mac /ApoE −/− macrophages, whereas SIRT1 overexpression rescued TIMP3 expression and inhibited ADAM17 expression. Our data suggest that SIRT1 deficiency may promote macrophage M1 polarization and regulate the TIMP3/ADAM17 pathway thus favoring atherosclerosis development, indicating an anti-atherosclerotic role of macrophage SIRT1. • Macrophage-specific SIRT1 deletion worsens atherosclerotic lesion in ApoE −/− mice. • Macrophage-specific SIRT1 deletion promotes M1-like macrophage in ApoE −/− mice. • SIRT1 overexpression regulates the TIMP3/ADAM17 pathway in macrophages. • Macrophage SIRT1 exhibits an anti-atherosclerotic role.