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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
1   First 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
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
3   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
,
Vincent Braunersreuther
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Fabienne Burger
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Sébastien Lenglet
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Graziano Pelli
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Federico Carbone
1   First 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
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Rodrigo Fraga-Silva
4   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Nikolaos Stergiopulos
4   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Claudia Monaco
5   Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
,
Christian Mueller
6   Department of Cardiology, University Hospital Basel, Switzerland
,
Sabrina Pagano
3   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
,
Franco Dallegri
1   First 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
2   Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, Geneva, Switzerland
,
Nicolas Vuilleumier
3   Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

Received: 15 December 2014

Accepted after major revision: 19 February 2015

Publication Date:
29 November 2017 (online)

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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

 

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