Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage

Increased expression of NAMPT in PBMC from patients with acute coronary syndrome and in inflammatory M1 macrophages

AbstractAimThe aim of the present study were to elucidate the role of NAMPT in atherosclerosis, by examine NAMPT expression in peripheral blood mononuclear cells (PBMC) in patients with coronary artery disease (CAD) and healthy controls and by examining the regulation and effect of NAMPT on macrophage polarization, hypothesizing that it could influence the polarization to inflammatory and resolving macrophages.Method and ResultsWe analyzed RNA levels of NAMPT in PBMC from CAD and healthy controls and found NAMPT to be increased in PBMC from patients with acute coronary syndrome (n = 39) compared to healthy controls (n = 20) and patients with stable CAD (n = 22). Within the PBMC NAMPT was correlated to several inflammatory cytokines and the antioxidant enzyme superoxide dismutase 2. In vitro cell experiments revealed that NAMPT is increased both intracellular and extracellular in inflammatory M1 macrophages compared to in anti-inflammatory M2 macrophages. In addition, inhibiting NAMPT enzymatic activity inhibited M1 polarization in macrophages.ConclusionBased on our in vivo and in vitro findings we suggest that NAMPT could contribute to systemic and plaque inflammation in atherosclerotic disorders at least partly through effect on macrophages

Increased levels of CCR7 ligands in carotid atherosclerosis: different effects in macrophages and smooth muscle cells

AIM: The homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 have recently been linked to atherogenesis. We investigated the expression of CCL19/CCL21/CCR7 in carotid atherosclerosis as well as the ability of these chemokines to modulate lipid accumulation in macrophages and vascular smooth muscle cell (SMC) phenotype.Methods and ResultsOur major findings were: (i) Patients with carotid atherosclerosis (n=158) had increased plasma levels of CCL21, but not of CCL19, compared to controls (n=20), with particularly high levels in symptomatic (n=99) as compared with asymptomatic (n=59) disease. (ii) Carotid plaques showed markedly increased mRNA levels of CCL21 and CCL19 in symptomatic (n=14) as compared with asymptomatic (n=7) patients, with CCR7 localized to macrophages and vascular SMC (immunohistochemistry). (iii) In vitro, CCL21, but not CCL19, increased the binding of modified LDL and promoted lipid accumulation in THP-1 macrophages. (iv). CCL19, but not CCL21, increased proliferation and release and activity of matrix metalloproteinase (MMP) 1 in vascular SMC. (v). The differential effects of CCL19 and CCL21 in macrophages and SMC seem to be attributable to divergent signaling pathways, with CCL19-mediated activation of AKT in SMC and CCL21-mediated activation of extracellular signal-regulated kinase 1/2 in macrophages. CONCLUSION: CCL19 and CCL21 are up-regulated in carotid atherosclerosis. The ability of CCL21 to promote lipid accumulation in macrophages and of CCL19 to induce proliferation and MMP-1 expression in vascular SMC could contribute to their pro-atherogenic potential