Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice

 

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Summary

Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.

• References

• 1 Van Gool F, Gallí M, Gueydan C. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 2009; 15: 206-210.
  CrossrefPubMedGoogle Scholar
• 2 Busso N, Karababa M, Nobile M. et al. Pharmacological inhibition of nicotina-mide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS One 2008; 3: e2267
  CrossrefPubMedGoogle Scholar
• 3 Bruzzone S, Fruscione F, Morando S. et al. Catastrophic NAD+ depletion in activated T lymphocytes through NAMPT inhibition reduces demyelination and disability in EAE. PLoS One 2009; 4: e7897
  CrossrefPubMedGoogle Scholar
• 4 Montecucco F, Bauer I, Braunersreuther V. et al. Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction. Antioxid Redox Signal 2013; 18: 630-641.
  CrossrefPubMedGoogle Scholar
• 5 Hasmann M, Schemainda I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res 2003; 63: 7436-7442.
  PubMedGoogle Scholar
• 6 Moschen AR, Gerner R, Schroll A, Fritz T, Kaser A, Tilg H. A key role for Pre-B cell colony-enhancing factor in experimental hepatitis. Hepatology 2011; 54: 675-686.
  CrossrefPubMedGoogle Scholar
• 7 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
  CrossrefPubMedGoogle Scholar
• 8 Koenen RR, Weber C. Chemokines: established and novel targets in atherosclerosis. EMBO Mol Med 2011; 3: 713-725.
  CrossrefPubMedGoogle Scholar
• 9 Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res 2012; 110: 875-888.
  CrossrefPubMedGoogle Scholar
• 10 Montecucco F, Di Marzo V, da Silva RF. et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 2012; 33: 846-856.
  CrossrefPubMedGoogle Scholar
• 11 Montecucco F, Lenglet S, Gayet-Ageron A. et al. Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischaemic stroke. Stroke 2010; 41: 1394-1404.
  CrossrefPubMedGoogle Scholar
• 12 Copin JC, da Silva RF, Fraga-Silva RA. et al. Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischaemic stroke, but not brain injury in mice. Cereb Blood Flow Metab 2013; 33: 490-498.
  CrossrefPubMedGoogle Scholar
• 13 Koenen RR, Weber C. Manipulating the chemokine system: therapeutic perspectives for atherosclerosis. Curr Opin Investig Drugs 2010; 11: 265-272.
  PubMedGoogle Scholar
• 14 Koenen RR, Weber C. Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 2010; 9: 141-153.
  CrossrefPubMedGoogle Scholar
• 15 Dahl TB, Yndestad A, Skjelland M. et al. Increased expression of visfatin in mac-rophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilisation. Circulation 2007; 115: 972-980.
  CrossrefPubMedGoogle Scholar
• 16 Cheng C, Tempel D, van Haperen R. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 2006; 113: 2744-2753.
  CrossrefPubMedGoogle Scholar
• 17 Lenglet S, Thomas A, Soehnlein O. et al. Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice. Arte-rioscler Thromb Vasc Biol 2013; 33: 215-223.
  CrossrefPubMedGoogle Scholar
• 18 van Leeuwen M, Gijbels MJ, Duijvestijn A. et al. Accumulation of myeloperox-idase-positive neutrophils in atherosclerotic lesions in LDLR-/- mice. Arte- rioscler Thromb Vasc Biol 2008; 28: 84-89.
  CrossrefPubMedGoogle Scholar
• 19 Polykratis A, van Loo G, Xanthoulea S, Hellmich M, Pasparakis M. Conditional targeting of tumor necrosis factor receptor-associated factor 6 reveals opposing functions of Toll-like receptor signalling in endothelial and myeloid cells in a mouse model of atherosclerosis. Circulation 2012; 126: 1739-1751.
  CrossrefPubMedGoogle Scholar
• 20 Skehan P, Storeng R, Scudiero D. et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990; 82: 1107-1112.
  CrossrefPubMedGoogle Scholar
• 21 Graeff R, Lee HC. A novel cycling assay for cellular cADP-ribose with nanomo- lar sensitivity. Biochem J 2002; 361: 379-384.
  CrossrefPubMedGoogle Scholar
• 22 Skokowa J, Lan D, Thakur BK. et al. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway. Nat Med 2009; 15: 151-158.
  CrossrefPubMedGoogle Scholar
• 23 Quercioli A, Mach F, Bertolotto M. et al. Receptor activator of NF- kB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability. Thromb Haemost 2012; 107: 124-139.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Shattuck RL, Wood LD, Jaffe GJ, Richmond A. MGSA/GRO transcription is differentially regulated in normal retinal pigment epithelial and melanoma cells. Mol Cell Biol 1994; 14: 791-802.
  CrossrefPubMedGoogle Scholar
• 25 Wood LD, Farmer AA, Richmond A. HMGI(Y) and Sp1 in addition to NF- kappa B regulate transcription of the MGSA/GRO alpha gene. Nucleic Acids Res 1995; 23: 4210-4219.
  CrossrefPubMedGoogle Scholar
• 26 Ohtsuka T, Kubota A, Hirano T. et al. Glucocorticoid-mediated gene suppression of rat cytokine-induced neutrophil chemoattractant CINC/gro, a member of the interleukin-8 family, through impairment of NF-kappa B activation. J Biol Chem 1996; 271: 1651-1659.
  CrossrefPubMedGoogle Scholar
• 27 Pierce JW, Schoenleber R, Jesmok G. et al. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 1997; 272: 21096-21103.
  CrossrefPubMedGoogle Scholar
• 28 Olsen LS, Hjarnaa PJ, Latini S. et al. Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer 2004; 111: 198-205.
  CrossrefPubMedGoogle Scholar
• 29 Hassan SB, Lövborg H, Lindhagen E. et al. CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome. Anticancer Res 2006; 26: 4431-4436.
  PubMedGoogle Scholar
• 30 Esposito E, Impellizzeri D, Mazzon E. et al. The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. J Neuroinflammation 2012; 9: 66.
  CrossrefPubMedGoogle Scholar
• 31 Soehnlein O, Drechsler M, Döring Y. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilisation and recruitment of classical mono-cytes. EMBO Mol Med 2013; 5: 471-481.
  CrossrefPubMedGoogle Scholar
• 32 Boisvert WA, Rose DM, Johnson KA. et al. Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol 2006; 168: 1385-1395.
  CrossrefPubMedGoogle Scholar
• 33 Montecucco F, Lenglet S, Braunersreuther V. et al. Single administration of the CXC chemokine-binding protein Evasin-3 during ischaemia prevents myo-cardial reperfusion injury in mice. Arterioscler Thromb Vasc Biol 2010; 30: 1371-1377.
  CrossrefPubMedGoogle Scholar
• 34 Wan W, Murphy PM. Regulation of atherogenesis by chemokines and chemo-kine receptors. Arch Immunol Ther Exp 2013; 61: 1-14.
  CrossrefPubMedGoogle Scholar
• 35 Drechsler M, Megens RT, van Zandvoort M. et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122: 1837-1845.
  CrossrefPubMedGoogle Scholar
• 36 Shimomura I, Shimano H, Korn BS. et al. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsatu-rated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 1998; 273: 35299-35306.
  CrossrefPubMedGoogle Scholar

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