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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 atherosclerotic 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 atherosclerotic 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.

Original publication

DOI

10.1160/th14-12-1039

Type

Journal article

Journal

Thrombosis and haemostasis

Publication Date

08/2015

Volume

114

Pages

410 - 422

Addresses

Fabrizio Montecucco, MD, PhD, Avenue de la Roseraie 64, Division of Laboratory Medicine and Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland, Tel.: +41 22 38 27 238, Fax: +41 22 38 27 245, E mail: fabrizio.montecucco@unige.ch.

Keywords

Myocardium, Animals, Mice, Knockout, Mice, Myocardial Ischemia, Myocardial Infarction, Aortic Diseases, Disease Susceptibility, Necrosis, Collagen, Lipids, Apolipoprotein A-I, Apolipoproteins E, Immunoglobulin G, Troponin I, Autoantibodies, Telemetry, Immunization, Passive, Signal Transduction, Male, Toll-Like Receptor 2, Toll-Like Receptor 4, Plaque, Atherosclerotic