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, Table of Contents

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

Authors

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

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

Full Text

References

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Supplementary Material

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