title: Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK.
abstract: A significant amount of myocardial damage during a myocardial infarction (MI) occurs during the reperfusion stage, termed ischaemia/reperfusion (I/R) injury, and accounts for up to 50% of total infarcted tissue post-MI. During the reperfusion phase, a complex interplay of multiple pathways and mechanisms is activated, which ultimately leads to cell death, primarily through apoptosis. There is some evidence from a lupus mouse model that lupus IgG, specifically the antiphospholipid (aPL) antibody subset, is pathogenic in mesenteric I/R injury. Furthermore, it has previously been shown that the immunodominant epitope for the majority of circulating pathogenic aPLs resides in the N-terminal domain I (DI) of beta-2 glycoprotein I (β2GPI). This study describes the enhanced pathogenic effect of purified IgG derived from patients with lupus and/or the antiphospholipid syndrome in a cardiomyocyte H/R in vitro model. Furthermore, we have demonstrated a pathogenic role for aPL containing samples, mediated via aPL-β2GPI interactions, resulting in activation of the pro-apoptotic p38 MAPK pathway. This was shown to be inhibited using a recombinant human peptide of domain I of β2GPI in the fluid phase, suggesting that the pathogenic anti-β2GPI antibodies in this in vitro model target this domain.
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.|Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK.
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Bourke
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonnell
authors.affiliation: Biochemistry Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health & Great Ormond Street Hospital, University College London, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: McCormick
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.
authors.forename: Charis
authors.initials: C
authors.lastname: Pericleous
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Ripoll
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Giles
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Medical and Molecular Biology Unit, University College London, London, UK.
authors.forename: Anastasis
authors.initials: A
authors.lastname: Stephanou
authors.affiliation: Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, UK.|Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Ioannou
mesh_terms: D000328:Adult; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology; D053482:beta 2-Glycoprotein I / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
chemical_list: D017152:Antibodies, Antiphospholipid; D007074:Immunoglobulin G; D053482:beta 2-Glycoprotein I; D048051:p38 Mitogen-Activated Protein Kinases