VNN1 promotes atherosclerosis progression in apoE−/− mice fed a high-fat/high-cholesterol diet

Atherosclerosis is a multistep process in which apoptosis, lipids, inflammatory cells, and mediators orchestrate the formation and progression of plaques, which can lead to stroke and/or heart attack (1, 2). Epidemiologic studies have suggested that lipid abnormalities in blood are key risk factors for the development of atherosclerosis. The HDL-cholesterol (HDL-C) level is inversely correlated with the prevalence of coronary events and therefore has a cardioprotective effect (2, 3). It is now well accepted that atherosclerosis is not only a disorder of lipid metabolism, but also a chronic inflammatory disease. Inflammatory processes are involved at all stages of the atherosclerotic development, from lesion initiation to plaque rupture (4, 5). In addition, proapoptotic and antiapoptotic mechanisms contribute to the development and progression of atherosclerosis (6). For example, apoptosis of endothelial cells and smooth muscle cells is detrimental for plaque stability. Functional roles of macrophage apoptosis in atherosclerosis depend on the stages of plaque development. In advanced lesions, macrophage apoptosis increases, and advanced lesional macrophage apoptosis is associated with vulnerable plaques: plaque necrosis (7). However, in early atherosclerosis, macrophages play a proatherogenic role, and the turnover of macrophages by apoptosis limits lesion development (8). Therefore, factors that act to lower levels of cholesterol, limit inflammation, and selectively induce macrophage apoptosis in this setting may prove to be beneficial in reducing disease progression. Vanin-1 (VNN1) is a glycosylphosphatidyl inositol-anchored pantetheinase that is highly expressed in the liver, gut, and kidney. It can catalyze the hydrolysis of pantetheine into cysteamine and pantothenic acid (vitamin B5) (9). Functional studies have suggested a role for VNN1 in oxidative stress, inflammation, and cell migration (10–13). For example, clinical investigations indicated that the levels of VNN1 were increased in the urine and blood of diabetic patients (14). VNN1 pantetheinase contributes to temporal and local tissue adaptation to needs and damage and participates in tissue tolerance to stress (15). Gensollen et al. (13) found that functional polymorphic positions in the VNN1 locus are direct targets for nuclear factors that might regulate the levels of VNN1 in colon and this would be linked to inflammatory bowel diseases susceptibility. These effects of VNN1 have attracted attention because evidence from in vitro systems and clinical studies suggests that it is a key activator for hepatic gluconeogenesis (14, 16). Importantly, the link between VNN1 and lipid metabolism has been revealed. For example, van Diepen et al. (17) showed that PPARα is the regulator of the expression and activity of VNN1 in the liver, which have key roles in the prevention of development of steatosis in response to fasting. A clinical study showed that VNN1 gene expression and the G-137T variant are associated with HDL-C levels in Mexican children, particularly in prepubertal girls (18). A sequencing effort yielded four SNPs in the VNN1 promoter region showed a high correlation with transcript abundance and HDL-C levels (19). However, these findings are descriptive, and the detailed mechanism through which VNN1 regulates lipid metabolism remains unknown. In the present study, we demonstrated that oxidized LDL (Ox-LDL) could significantly induce VNN1 expression through an ERK1/2/cyclooxygenase-2 (COX-2)/PPARα signaling pathway. In addition, VNN1 promotes accumulation of cholesteryl esters by inhibiting expression of PPARγ and liver X receptor (LXR) α in THP-1 macrophage-derived foam cells Moreover, VNN1 attenuates Ox-LDL-induced apoptosis through upregulation of expression of p53 and downregulation of B-cell lymphoma-2 (BCL-2) in vascular smooth muscle cells (VSMCs). Consistent with this hypothesis, development of atherosclerotic lesions was increased significantly by infection of apoE−/− mice with lentivirus (LV) encoding mouse VNN1 (LV-VNN1).