inflammation; anti-apolipoprotein A-1 autoantibodies; cardiovascular disease; atherogenesis
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Background: Immune-mediated inflammation plays a major role in atherosclerosis and atherothrombosis, two essential features for cardiovascular disease (CVD) development, currently considered as the leading cause of death in the Western world. There is accumulating evidence showing that humoral autoimmunity might play an important role in CVD, and that some auto-antibodies could represent emerging cardiovascular risk factors. We demonstrated that IgG auto-antibodies against apolipoprotein A-1 (apoA-1), the major proteic fraction of high-density lipoprotein (HDL), were present at high titres in a significant subset of patients suffering from myocardial infarction (MI) (10-20%) and rheumatoid arthritis (RA) (17%), were associated to more vulnerable carotid atherosclerotic plaques in humans and independently predicted cardiovascular complications. In those clinical studies we demonstrated significant associations between high levels of those antibodies and some pro-inflammatory cytokines considered as possible systemic marker of atherosclerotic plaque instability (TNF-a; IL-6; IL-8, MMP-9, and oxidised low-density lipoprotein). Concomitantly, our data from in vitro studies suggest that anti-apoA-1 IgG i) directly induces the production TNF-a, IL-6, IL-8, and MMP-9 by human macrophages, possibly trough the engagement of Toll-like receptor (TLR)-2/CD14 complex, ii) directly affects basal heart rate by an unknown but aldosterone-specific and dependent mechanism in vitro, that can by prevented by specific therapeutic interventions in vitro. Finally, we demonstrated that passive immunization with anti-apoA-1 IgG in apoE -/- mice increased atherogenesis and atherosclerotic plaque vulnerability.Hypotheses: Anti-apoA-1 IgG may represent a new modifiable cardiovascular risk factor promotingatherogenesis , and atherothrombosis. Specific aims:1. To confirm in vitro that the complex CD14/TLR2 is required for anti-apoA-1 IgG their pro-inflammatory and chronotropic effects2. To determine the effect of anti-apoA-1 IgG passive immunization in apoE-/- mice mutated for TLR2 and 4 on: i) atherogenesis, ii) on mice survival and malignant arythmia occurrence.3. To evaluate the incremental diagnostic and prognostic value of anti-apoA-1 in acute chest pain patients for rapid myocardial infarction exclusion on the complete APACE multicentre cohort, including 1600 patients.Experimental Design and Methods: Pro-inflammatory and pro-arythmogenic properties of anti-apoA-1 IgG will be tested in vitro on human macrophages, HEKblue2 and 4 cells, and neonatal rat cardiomyocytes, respectively. Passive immunisation protocol with anti-apoA-1 IgG in apoE-/-, apoE/TLR2 -/- and apoE/TLR4 -/- mice equipped with telemetry allowing continuous electrocardiographic (ECG) recordings during one month will be performed. Readout systems will include ELISA, FACS analysis, immunohistochemistry and confocal microscope for in vitro experiments, and ECG mortality rate monitoring for mice studies. The diagnostic and prognostic values of anti-apoA-1 IgG for MI will be assessed on APACE (NCT00470587) cohort.Expected Relevance: This collaborative translational research project between Geneva and Basel University Hospitals combining in vitro, in vivo and clinical studies will generate benchmark high quality data allowing to answer the debated question concerning the clinical relevance of those autoantibodies in cardiovascular-related complication in humans.