Treatment with the GPR55 antagonist CID16020046 increases neutrophil activation in mouse atherogenesis

Fabrizio Montecucco; Alexander I. Bondarenko; Sébastien Lenglet; Fabienne Burger; Fabiana Piscitelli; Federico Carbone; Aline Roth; Luca Liberale; Franco Dallegri; Karim J. Brandt; Rodrigo A. Fraga-Silva; Nikolaos Stergiopulos; Vincenzo Di Marzo; François Mach

doi:10.1160/TH16-02-0139

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 116(05): 987-997
DOI: 10.1160/TH16-02-0139

Atherosclerosis and Ischaemic Disease

Schattauer GmbH

Treatment with the GPR55 antagonist CID16020046 increases neutrophil activation in mouse atherogenesis

Fabrizio Montecucco

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy

²IRCCS AOU San Martino - IST, Genova, Genoa, Italy

,

Alexander I. Bondarenko

³Circulatory Physiology Department, Bogomoletz Institute of Physiology, Kiev, Ukraine

,

Sébastien Lenglet

⁴Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Fabienne Burger

⁴Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Fabiana Piscitelli

⁵Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Naples, Italy

,

Federico Carbone

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Aline Roth

⁴Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Luca Liberale

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Franco Dallegri

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Karim J. Brandt

⁴Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Rodrigo A. Fraga-Silva

⁶Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Nikolaos Stergiopulos

⁶Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Vincenzo Di Marzo^*

⁵Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Naples, Italy

,

François Mach^*

⁴Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

› Institutsangaben

Abstract

Summary

Endocannabinoids modulate atherogenesis by triggering different receptors. Recently, orphan G protein-coupled receptors (GPRs) were suggested to be activated by endocannabinoids, possibly regulating vasorelaxation. Here, we investigated whether GPR55 antagonism with CID16020046 would impact on atherosclerotic size and inflammation in two mouse models of early and more advanced atherogenesis. Eleven-week old ApoE^−/− mice were fed either a normal diet ([ND] for 16 weeks) or a high-cholesterol diet ([HD] for 11 weeks), resulting in different degrees of hypercholesterolaemia and size of atherosclerosis. CID16020046 (0.5 mg/kg) or vehicle were intraperitoneally administrated five times per week in the last three weeks before euthanasia. Treatment with CID1602004 was well-tolerated, but failed to affect atherosclerotic plaque and necrotic core size, fibrous cap thickness, macrophage and smooth muscle cell content as well as Th cell polarisation. In ND mice, treatment with CID1602004 was associated with increased chemokine production, neutrophil and MMP-9 intraplaque content as well as reduced collagen as compared to vehicletreated animals. In HD mice, CID1602004 increased intraplaque MMP-9 and abrogated collagen content without affecting neutrophils. In vitro, serum from CID1602004-treated ND mice increased mouse neutrophil chemotaxis towards CXCL2 as compared to serum from vehicletreated animals. CID1602004 dose-dependently induced neutrophil degranulation that was reverted by co-incubation with the GPR55 agonist Abn-CBD. In supernatants from degranulation experiments, increased levels of the endocannabinoid and putative GPR55 ligand anandamide (AEA) were found, suggesting its possible autocrine control of neutrophil activity. These results indicate that GPR55 is critical for the negative control of neutrophil activation in different phases of atherogenesis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Atherosclerosis - endocannabinoids - receptors - neutrophil

Volltext

Referenzen

References
1 Ouweneel AB, Van Eck M. Lipoproteins as modulators of atherothrombosis: From endothelial function to primary and secondary coagulation. Vascul Pharmacol 2015;
2 Ketelhuth DF, Hansson GK. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost 2011; 106: 779-786.
3 Ray KK, Kastelein JJ, Boekholdt SM. et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014; 35: 960-968.
4 Montecucco F, Di Marzo V. At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol Sci 2012; 33: 331-340.
5 Li YF, Li RS, Samuel SB. et al. Lysophospholipids and their G protein-coupled receptors in atherosclerosis. Front Biosci 2016; 21: 70-88.
6 Steffens S, Veillard NR, Arnaud C. et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434: 782-786.
7 Quercioli A, Pataky Z, Vincenti G. et al. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 2011; 32: 1369-1378.
8 Stancic A, Jandl K, Hasenöhrl C. et al. The GPR55 antagonist CID16020046 protects against intestinal inflammation. Neurogastroenterol Motil 2015; 27: 1432-1445.
9 Oka S, Nakajima K, Yamashita A. et al. Identification of GPR55 as a lysophos-phatidylinositol receptor. Biochem Biophys Res Commun 2007; 362: 928-934.
10 Ryberg E, Larsson N, Sjögren S. et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007; 152: 1092-1101.
11 Lauckner JE, Jensen JB, Chen HY. et al. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA 2008; 105: 2699-2704.
12 Zhao P, Abood ME. GPR55 and GPR35 and their relationship to cannabinoid and lysophospholipid receptors. Life Sci 2013; 92: 453-457.
13 Piñeiro R, Falasca M. Lysophosphatidylinositol signalling: new wine from an old bottle. Biochim Biophys Acta 2012; 1821: 694-705.
14 AlSuleimani YM, Hiley CR. The GPR55 agonist lysophosphatidylinositol relaxes rat mesenteric resistance artery and induces Ca(2+) release in rat mesen-teric artery endothelial cells. Br J Pharmacol 2015; 172: 3043-3057.
15 Chiurchiù V, Lanuti M, De Bardi M. et al. The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells. Int Immunol 2015; 27: 153-160.
16 Balenga NA, Aflaki E, Kargl J. et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Res 2011; 21: 1452-1469.
17 Hiley CR, Kaup SS. GPR55 and the vascular receptors for cannabinoids. Br J Pharmacol 2007; 152: 559-561.
18 Lanuti M, Talamonti E, Maccarrone M. et al. Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses, while Reducing Cholesterol Efflux from Human Macrophages. PLoS One 2015; 10: 0126839.
19 Borrelli F, Romano B, Petrosino S. et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br J Pharmacol 2015; 172: 142-158.
20 Li K, Feng JY, Li YY. et al. Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 2013; 42: 123-129.
21 Schicho R, Bashashati M, Bawa M. et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis 2011; 17: 1651-1664.
22 Al Suleimani YM, Al Mahruqi AS, Hiley CR. Mechanisms of vasorelaxation induced by the cannabidiol analogue compound O-1602 in the rat small mesen-teric artery. Eur J Pharmacol 2015; 765: 107-114.
23 Montecucco F, Lenglet S, Carbone F. et al. Treatment with KLEPTOSE® CRYS-MEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response. Vascul Pharmacol 2015; 72: 197-208.
24 Montecucco F, Vuilleumier N, Pagano S. et al. Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability. Eur Heart J 2011; 32: 412-421.
25 Winnik S, Gaul DS, Preitner F. et al. Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development. Basic Res Cardiol 2014; 109: 399.
26 Seneviratne AN, Cole JE, Goddard ME. et al. Low shear stress induces M1 mac-rophage polarization in murine thin-cap atherosclerotic plaques. J Mol Cell Cardiol 2015; 89: 168-172.
27 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.
28 Montecucco F, Lenglet S, Braunersreuther V. et al. Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice. Arterioscler Thromb Vasc Biol 2010; 30: 1371-1377.
29 Lecut C, Frederix K, Johnson DM. et al. P2×1 ion channels promote neutrophil chemotaxis through Rho kinase activation. J Immunol 2009; 183: 2801-2809.
30 Matias I, Carta G, Murru E. et al. Effect of polyunsaturated fatty acids on endoc-annabinoid and N-acyl-ethanolamine levels in mouse adipocytes. Biochim Bio-phys Acta 2008; 1781: 52-60.
31 Nencioni A, da Silva RF, Fraga-Silva RA. et al. Nicotinamide phosphoribosyltrans-ferase inhibition reduces intraplaque CXCL1 production and associated neutro-phil infiltration in atherosclerotic mice. Thromb Haemost 2014; 111: 308-322.
32 Wiesner P, Choi SH, Almazan F. et al. Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circ Res 2010; 107: 56-65.
33 Montecucco F, Matias I, Lenglet S. et al. Regulation and possible role of endoc-annabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis 2009; 205: 433-441.
34 Wendorff C, Wendorff H, Pelisek J. et al. Carotid Plaque Morphology Is Significantly Associated With Sex, Age, and History of Neurological Symptoms. Stroke 2015; 46: 3213-3219.
35 Bot PT, Grundmann S, Goumans MJ. et al. Forkhead box protein P1 as a downstream target of transforming growth factor-β induces collagen synthesis and correlates with a more stable plaque phenotype. Atherosclerosis 2011; 218: 33-43.
36 Drechsler M, Megens RT, van Zandvoort M. et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122: 1837-1845.
37 Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res 2012; 110: 875-888.
38 Nguyen DH, Giri B, Collins G. et al. Dynamic reorganization of chemokine receptors, cholesterol, lipid rafts, and adhesion molecules to sites of CD4 engagement. Exp Cell Res 2005; 304: 559-569.
39 Balenga NA, Martínez-Pinilla E, Kargl J. et al. Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. Br J Pharmacol 2014; 171: 5387-5406.

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