Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice.

Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis. First, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. We also found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE(/) mice fed a high-fat diet for 12 weeks. Next, PGRN(/)ApoE(/) mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN(/)ApoE(/) mice exhibited severe atherosclerotic lesions compared with PGRN(/)ApoE(/) mice, despite their anti-atherogenic lipid profile. These results are partly due to enhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins. PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.