Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4

Fabrizio Montecucco; Vincent Braunersreuther; Fabienne Burger; Sébastien Lenglet; Graziano Pelli; Federico Carbone; Rodrigo Fraga-Silva; Nikolaos Stergiopulos; Claudia Monaco; Christian Mueller; Sabrina Pagano; Franco Dallegri; François Mach; Nicolas Vuilleumier

doi:10.1160/TH14-12-1039

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(02): 410-422
DOI: 10.1160/TH14-12-1039

Atherosclerosis and Ischaemic Disease

Schattauer GmbH

Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4

Fabrizio Montecucco

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

,

Vincent Braunersreuther

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Fabienne Burger

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Sébastien Lenglet

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Graziano Pelli

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Federico Carbone

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Rodrigo Fraga-Silva

⁴Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Nikolaos Stergiopulos

⁴Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Claudia Monaco

⁵Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

,

Christian Mueller

⁶Department of Cardiology, University Hospital Basel, Switzerland

,

Sabrina Pagano

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

,

Franco Dallegri

¹First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

,

François Mach

²Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland

,

Nicolas Vuilleumier

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

› Author Affiliations

Abstract

Summary

Auto-antibodies to apolipoprotein A-1 (anti-apoA-1 IgG) were shown to promote inflammation and atherogenesis, possibly through innate immune receptors signalling. Here, we aimed at investigating the role of Toll-like receptors (TLR) 2 and 4 on anti-apoA-1 IgG-induced athero-sclerotic plaque vulnerability, myocardial necrosis and mortality in mice. Adult male apolipoprotein E knockout (ApoE)^-/-(n=72), TLR2^-/-ApoE^-/- (n=36) and TLR4^-/-Apo^-/- (n=28) mice were intravenously injected with 50 µg/mouse of endotoxin-free polyclonal anti-apoA-1 IgG or control isotype IgG (CTL IgG) every two weeks for 16 weeks. Atherosclerotic plaque size and vulnerability were assessed by histology. Myocardial ischaemia and necrosis, respectively, were determined by electrocardiographic (ECG) changes assessed by telemetry and serum troponin I (cTnI) measurements. Impact on survival was assessed by Kaplan-Meier analyses. In ApoE^-/- mice, anti-apoA-1 IgG passive immunisation enhanced histological features of athero-sclerotic plaque vulnerability (increase in neutrophil and MMP-9 and reduction in collagen content), induced a substantial cTnI elevation (p=0.001), and increased mortality rate by 23 % (LogRank, p=0.04) when compared to CTL IgG. On a subgroup of ApoE^-/-mice equipped with telemetry (n=4), a significant ST-segment depression was noted in anti-apoA-1 IgG-treated mice when compared to CTL IgG recipients (p< 0.001), and an acute ST-segment elevation myocardial infarction preceding mouse death was observed in one case. The deleterious effects of anti-apoA-1 IgG on atherosclerotic plaque vulnerability, myocardial necrosis and death were partially reversed in TLR2^-/-ApoE^-/- and TLR4^-/-ApoE^-/- backgrounds. In conclusion, anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways.

Keywords

Antibody - acute myocardial infarction - mortality - atherogenesis

Full Text

References

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