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
1   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
2   IRCCS AOU San Martino - IST, Genova, Genoa, Italy
,
Alexander I. Bondarenko
3   Circulatory Physiology Department, Bogomoletz Institute of Physiology, Kiev, Ukraine
,
Sébastien Lenglet
4   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Fabienne Burger
4   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Fabiana Piscitelli
5   Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Naples, Italy
,
Federico Carbone
1   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Aline Roth
4   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Luca Liberale
1   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Franco Dallegri
1   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
,
Karim J. Brandt
4   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Rodrigo A. Fraga-Silva
6   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Nikolaos Stergiopulos
6   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Vincenzo Di Marzo*
5   Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Naples, Italy
,
François Mach*
4   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
› Author Affiliations
Financial support: This study was supported by European Commission (FP7-INNOVATION I HEALTH-F2–2013–602114; Athero-B-Cell: Targeting and exploiting B cell function for treatment in cardiovascular disease). This work was supported by Swiss National Science Foundation Grants to Prof. F. Montecucco (#310030_152639/1) and to Prof. F. Mach (#IZ73Z0_152578).
Further Information

Publication History

Received: 19 February 2016

Accepted after major revision: 04 July 2016

Publication Date:
30 November 2017 (online)

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.

* These authors equally contributed as last to this work.