Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice (original) (raw)
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Atherosclerosis, 2012
Objectives: Based on the newly recognized role of the homeostatic chemokines in inflammation, we hypothesized that CXCL13 could modulate atherogenesis and plaque destabilization. Methods: The study included in vivo analyses in patients with carotid atherosclerosis and in vitro experiments in cells involved in atherogenesis (ie, monocytes/macrophages, vascular smooth muscle cells [SMC], and platelets). Results: Our main findings were: (i) Patients with carotid atherosclerosis (n ¼ 130) had increased plasma levels of CXCL13 with particularly high levels in symptomatic disease. (ii) CXCL13 showed increased expression within atherosclerotic carotid plaques as compared with non-atherosclerotic vessels. (iii) Within the atherosclerotic lesions, CXCR5 and CXCL13 were expressed by macrophages and SMC in all stages of plaque progression. (iv) Releasate from activated platelets and toll-like receptor activation enhanced the expression of CXCL13 in THP-1 monocytes and primary monocytes. (v) In vitro, CXCL13 exerted anti-apoptotic effects in primary monocytes, THP-1 macrophages, and vascular SMC. (vi) CXCL13 increased arginase-1, transforming growth factor-b, and interleukin-10 expression in THP-1 cells and in samples from isolated carotid plaques. Conclusion: Levels of CXCL13 are increased in carotid atherosclerosis both systemically and within the atherosclerotic lesion. Based on our in vitro findings, we hypothesize a potential plaque stabilizing effects of CXCL13-CXCR5 interaction.
CXCR4 blockade induces atherosclerosis by affecting neutrophil function
Journal of Molecular and Cellular Cardiology, 2014
44 45 46 47 48 65 inflammatory and matrix-stabilizing effects of SDF-1α [8].Thisnotion 66 was corroborated by recent study by us showing that systemic blockade 67 of CXCR4 by the CXCR4 antagonist AMD3465 enhanced plaque initiation 68 due to increased neutrophil recruitment [11].
Arteriosclerosis, Thrombosis, and Vascular Biology, 2008
Objective-We examined the role of the CXCR2 ligand growth-related oncogene (GRO) ␣ in human atherosclerosis. Methods and Results-GRO␣ levels were examined by enzyme immunoassay, real-time quantitative RT-PCR, and cDNA microarrays. The in vitro effect of statins on GRO␣ was examined in endothelial cells and THP-1 macrophages. Our main findings were: (1) GRO␣ was among the 10 most differentially expressed transcripts comparing peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) and healthy controls.
CXCL4-Induced Macrophages: A Novel Therapeutic Target in Human Atherosclerosis?
Atherogenesis, 2012
Atherosclerosis and its consequences (i.e. myocardial infarction and cardiac death) remain the major cause of morbidity and mortality in Western countries (Roger et al. 2011). Despite clinical advances that have substantially improved outcomes in patients suffering from coronary artery disease, including pharmacological interventions (e.g. novel anti platelet therapies, statins, etc.) as well as interventional and surgical therapies (e.g. drug-eluting stents), there is still a huge demand for improved diagnostic tools to identify patients at risk for adverse events as well as therapeutic means to prevent adverse events in these patients. Biomarkers such as high sensitivity CRP (Ridker 2007) or high sensitivity troponin T (Kurz et al. 2011) have brought some improvement in identifying patients requiring more intense treatment; however, the clinical need for better tools remains. An important concept that may help to improve clinical care for patients with coronary artery disease is the inducement of plaque stability. Atherosclerotic lesions can show features of plaque stability or plaque instability (Naghavi et al. 2003a, Naghavi et al. 2003b). Stable plaques are characterized by a thick fibrous cap and a small necrotic core. By contrast, unstable plaques display a thin fibrous cap and a large necrotic core consisting of apoptotic macrophages, foam cells, and smooth muscle cells. Unstable plaques are more likely to rupture, and plaque rupture may subsequently result in thrombosis and occlusion of the vessel leading to a myocardial infarction or stroke. A promising approach to identify potential markers of plaque instability may be the study of atherogenesis on a cellular and molecular level. During the development of atherosclerotic lesions, blood monocytes adhere to the activated endothelium, transmigrate into the subendothelial space, and differentiate towards macrophages, dendritic cells, or foam cells (Galkina & Ley 2009). Among the various leukocyte types involved in atherogenesis, monocytes and monocyte-derived macrophages represent the major fraction. The monocyte-macrophage differentiation process is affected by the extracellular matrix as well as by the combination of chemokines and cytokines representing the micromilieu of the plaque (Shashkin et al. 2005). In addition, cell-cell interactions may also affect the fate of monocytes within the atherosclerotic plaque. Monocyte-derived cells secrete chemokines, cytokines, and other mediators, leading to attraction of other immune cells and thereby promoting plaque progression and plaque instability (Shashkin et al. 2005). While it was initially thought that monocyte-derived macrophages represent a homogenous population www.intechopen.com
Arteriosclerosis, thrombosis, and vascular biology, 2017
Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)(+) generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPT(hi)), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPT(hi) phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNA...
Endothelial Cell-Specific NF-κB Inhibition Protects Mice from Atherosclerosis
Cell Metabolism, 2008
Atherosclerosis is a progressive disorder of the arterial wall and the underlying cause of cardiovascular diseases such as heart attack and stroke. Today, atherosclerosis is recognized as a complex disease with a strong inflammatory component. The nuclear factor-kB (NF-kB) signaling pathway regulates inflammatory responses and has been implicated in atherosclerosis. Here, we addressed the function of NF-kB signaling in vascular endothelial cells in the pathogenesis of atherosclerosis in vivo. Endotheliumrestricted inhibition of NF-kB activation, achieved by ablation of NEMO/IKKg or expression of dominant-negative IkBa specifically in endothelial cells, resulted in strongly reduced atherosclerotic plaque formation in ApoE À/À mice fed with a cholesterolrich diet. Inhibition of NF-kB abrogated adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Thus, endothelial NF-kB signaling orchestrates proinflammatory gene expression at the arterial wall and promotes the pathogenesis of atherosclerosis.
Atherosclerotic Plaque Stability Is Affected by the Chemokine CXCL10 in Both Mice and Humans
International Journal of Inflammation, 2011
Background. The chemokine CXCL10 is specifically upregulated during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and humans. Methods and Results. In ApoE −/− mice, we induced unstable plaque with using a flow-altering device around the carotid artery. From week 1 to 4, mice were injected with a neutralizing CXCL10 antibody. After 9 weeks, CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (P = 0.002), smooth muscle cell content increased 2-fold (P = 0.03), while macrophage MHC class II expression decreased by 50% (P = 0.005). Also, the size of necrotic cores decreased by 41% (P = 0.01). In 106 human carotid endarterectomy specimens we found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, P = 0.003), with high macrophage, low smooth muscle cell, and low collagen content. Conclusions. In the present study we showed that CXCL10 is associated with the development of vulnerable plaque in human and mice. We conclude that CXCL10 might provide a new lead towards plaque-stabilizing therapy.
Antioxidants & Redox Signaling, 2013
Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD +) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. Results: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD +-dependent deacetylase in the production of this chemokine. Innovation: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation-and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. Conclusions: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice. Antioxid. Redox Signal. 18, 630-641.
Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
Objective-Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis. Approach and Results-Treatment with F1, an amino terminus-modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe −/− and Ldlr −/− proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe −/− mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe −/− mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of Apoe −/− mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype.