Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK
Open Access
- 12 January 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 8 (1), e2549
- https://doi.org/10.1038/cddis.2016.235
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.Keywords
This publication has 45 references indexed in Scilit:
- Evaluating the conformation of recombinant domain I of β2-glycoprotein I and its interaction with human monoclonal antibodiesMolecular Immunology, 2011
- Effects of Polyclonal IgG Derived from Patients with Different Clinical Types of the Antiphospholipid Syndrome on Monocyte Signaling PathwaysThe Journal of Immunology, 2010
- Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemiaJournal of Cellular and Molecular Medicine, 2009
- Arteriosclerosis obliterans associated with anti-cardiolipin antibody / 2-glycoprotein I antibodies as a strong risk factor for ischaemic heart disease in patients with systemic lupus erythematosusRheumatology, 2008
- Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human β2‐glycoprotein I: Mutation studies including residues R39 to R43Arthritis & Rheumatism, 2007
- International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)Journal of Thrombosis and Haemostasis, 2006
- Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF‐κB/Rel proteins via the p38 mitogen‐activated protein kinase pathway, and of the MEK‐1/ERK pathwayArthritis & Rheumatism, 2005
- Involvement of p38 MAPK in the up‐regulation of tissue factor on endothelial cells by antiphospholipid antibodiesArthritis & Rheumatism, 2005
- The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti- 2Glycoprotein I antibodiesInternational Immunology, 2004
- Role of p38 MAP Kinase in Myocardial StressJournal of Molecular and Cellular Cardiology, 1998