Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function

Bermúdez, Beatriz; Dahl, Tuva B.; Medina, Indira; Groeneweg, Mathijs; Holm, Sverre; Paz, Sergio Montserrat-de la; Rousch, Mat; Otten, Jeroen J. T.; Hérias, Veronica; Varela, Lourdes M.; Ranheim, Trine; Yndestad, Arne; Ortega‐Gómez, Almudena; Abia, Rocı́o; Nagy, László; Aukrust, Pål; Muriana, Francisco J.G.; Halvorsen, Bente; Biessen, Erik A. L.

doi:10.1161/atvbaha.116.308187

Cited by 37 publications

(36 citation statements)

References 27 publications

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“…26) However, another study showed that the overexpression of NAMPT in leukocytes in atherosclerotic patients can inhibit atherosclerosis by the regulation of PPARγ dependent monocyte differentiation. 27) The results of this study showed that the levels of iNAMPT and Sirt1 in PBMC and NAD+, eNAMPT in plasma increased in the ACS patients, which suggested that the NAMPT/NAD+/Sirt1 signaling pathway was upregulated in the ACS patients. Sirt1 is a histone deacetylase that depends on NAD+; it has the function of inhibiting apoptosis, inhibiting inflammatory reaction, and inhibiting oxidative stress injury.…”

Section: Discussionmentioning

confidence: 63%

Nicotinamide Phosphate Transferase (NAMPT) Increases in Plasma in Patients with Acute Coronary Syndromes, and Promotes Macrophages to M2 Polarization

et al. 2018

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Atherosclerosis is an inflammatory disease; monocytes and macrophages play an important role in the progression of this disease. However, the mechanisms are not fully understood yet. Nicotinamide phosphate transferase (NAMPT) is the rate limiting enzyme in the synthesis of NAD, but extracellular NAMPT shows the characteristics of cytokines/adipokines, suggesting that it may be a link between metabolism and inflammation. In this study, we compared the expression levels of the NAMPT/NAD+/Sirt1 signaling pathway as well as NAMPT, CRP and IL-6 in the peripheral blood mononuclear cell (PBMC), and plasma in patients with acute coronary syndromes and healthy subjects, and analyzed their association with macrophage polarization. The relationship between eNAMPT and iNAMPT and the polarization of macrophages was analyzed by NAD+, NAMPT blocker, and neutralizing antibody treatment. The results showed that the expression of the NAMPT/NAD+/Sirt1 signaling pathway was up-regulated in the peripheral blood of patients with ACS. Inhibition of iNAMPT expression can reduce M1 polarization; however, there was no significant effect on eNAMPT secretion and M2 polarization. Neutralizing eNAMPT by neutralizing antibodies can reduce M2 polarization and decrease the expression levels of IL-10, IL-13, IL-4 and IL-1ra. The addition of NAD+ in the cell culture supernatant had no significant effect on the polarization of M1 but increased the M2 polarization and the expression levels of IL-10 and IL-1ra. Our findings suggested that NAMPT is involved in the pathogenesis of atherosclerosis; the increased expression of eNAMPT in ACS patients may play a protective role by the up regulation of the NAMPT/NAD+/Sirt1 signaling pathway.

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Section: Discussionmentioning

confidence: 63%

Nicotinamide Phosphate Transferase (NAMPT) Increases in Plasma in Patients with Acute Coronary Syndromes, and Promotes Macrophages to M2 Polarization

et al. 2018

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“…In contrast, knockdown of PPAR␥ impairs M2 polarization and insulin signaling (10). It has been demonstrated that PPAR␥-dependent monocyte differentiation into M2 macrophage is beneficial to human carotid atherosclerosis (11). PPAR␥ activation by pioglitazone regulates M2 macrophage infiltration and stabilizes the neovessels in the infarct border zone, leading to a better outcome for patients after stroke (12).…”

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confidence: 99%

Peroxisome proliferator–activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization

Yao

Liu

Zhang

et al. 2018

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily and polarizes the macrophages into an anti-inflammatory M2 state. Integrins are transmembrane receptors that drive various cellular functions, including monocyte adhesion and foam cell formation. In this study, we first reported that the expression of integrins α and β was up-regulated by PPARγ activation in RAW264.7 cells and human peripheral blood monocytes. Luciferase reporter and ChIP assay revealed that PPARγ directly bound to the potential PPAR-responsive elements sites in the 5'-flanking regions of both murine and human integrin α and β genes, respectively. In addition, we showed that PPARγ augmented the ligation of integrins α and β Knockdown of integrin αβ by siRNA strategy or treatment with cilengitide, a potent inhibitor of integrin αβ, attenuated PPARγ-induced expression of Ym1 (chitinase-like protein 3), Arg1 (Arginase1), Fizz1 (resistin-like molecule RELMα), and other M2 marker genes, suggesting that the heterodimers of integrin αβ were involved in PPARγ-induced M2 polarization. In conclusion, these results provided novel evidence that PPARγ-mediated gene expression and the ensuing ligation of integrins α and β are implicated in macrophage M2 polarization.

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“…Recent studies have been focused on eNAMPT, which is thought to act as a pro‐inflammatory cytokine (Laiguillon et al, ). However, Lin et al () and our research group also reported that iNAMPT may have beneficial anti‐inflammatory properties (Bermudez et al, ). In the present study, this dual role of eNAMPT (visfatin) and iNAMPT has been explored by analyzing the concentration of visfatin/eNAMPT in the medium of cells and the relative mRNA levels of NAMPT/iNAMPT .…”

Section: Discussionmentioning

confidence: 79%

“…In the rescue route of nicotinamide adenine dinucleotide (NAD + ) generation, intracellular NAMPT ( iNAMPT ) appears to be the rate‐limiting enzyme (Montserrat‐de la Paz, Naranjo, et al, ). Previous studies have proved the significance of NAMPT‐mediated NAD + recycling, in cooperation with NAD + ‐dependent protein deacetylases (sirtuins), directly on the expression of peroxisome proliferator‐activated receptors ( PPARs ), NF‐κB , and endothelial NOS ( eNOS ); many data also provide evidence of an indirect role in metabolism, aging, inflammation, cell proliferation, and differentiation (Bermudez et al, ). Cells also produce NAMPT to create an extracellular supply (eNAMPT) with cytokine‐like activity (Dahl, Holm, Aukrust, & Halvorsen, ).…”

Section: Introductionmentioning

confidence: 99%

Minor compounds from virgin olive oil attenuate LPS‐induced inflammation via visfatin‐related gene modulation on primary human monocytes

et al. 2019

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We have analyzed the effects of minor compounds found in the unsaponifiable fraction (UF) and in the phenolic fraction (PF) of virgin olive oil (VOO) on LPS‐induced inflammatory response via visfatin modulation in human monocytes. For this purpose, monocytes were incubated with UF and PF at different concentrations and the pro‐inflammatory stimulus LPS for 24 hr; squalene (SQ) and hydroxytyrosol (HTyr), the main components in UF and PF, respectively, were also used. The relative expression of both pro‐inflammatory and anti‐inflammatory genes, as well as other genes related to the NAD+‐biosynthetic pathway was evaluated by RT‐qPCR; and the secretion of some of these markers was assessed by ELISA procedures. We found that UF, SQ, PF, and HTyr prevented from LPS‐induced dysfunctional gene expression and secretion via visfatin‐related gene modulation in human monocytes. These findings unveil a potential beneficial role for minor compounds of VOO in the prevention of inflammatory‐disorders. Practical application In this project, potential health benefits of VOO micronutrients (unsaponifiable and phenolic compounds) were confirmed through anti‐inflammatory assays. Our results reveal new interesting researching goals concerning nutrition by considering the role of bioactive VOO compounds in the prevention and progress of diseases related to inflammation.

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Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function

Abstract: This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.

Cited by 37 publications

References 27 publications

Nicotinamide Phosphate Transferase (NAMPT) Increases in Plasma in Patients with Acute Coronary Syndromes, and Promotes Macrophages to M2 Polarization

Nicotinamide Phosphate Transferase (NAMPT) Increases in Plasma in Patients with Acute Coronary Syndromes, and Promotes Macrophages to M2 Polarization

Peroxisome proliferator–activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization

Minor compounds from virgin olive oil attenuate LPS‐induced inflammation via visfatin‐related gene modulation on primary human monocytes

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