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.
Highlights
The antiphospholipid syndrome (APS) is characterised by the clinical syndrome of arterial and venous thrombosis and/or recurrent pregnancy morbidity in association with the presence of antiphospholipid antibodies.[1]
In vivo rat studies have shown that the number of terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL)-positive cardiomyocytes in I/R injury can be reduced by treatment with a caspase inhibitor,[15] resulting in a reduced infarct size indicating that apoptosis plays an important role in I/R-induced damage
A novel pathogenic role for aPL autoantibodies has been identified by demonstrating a pro-apoptotic effect within an in vitro model of cardiomyocyte H/R injury
Summary
The antiphospholipid syndrome (APS) is characterised by the clinical syndrome of arterial and venous thrombosis and/or recurrent pregnancy morbidity in association with the presence of antiphospholipid (aPL) antibodies.[1]. Myocardial infarction (MI) is an important cause of morbidity and mortality in systemic lupus erythematosus (SLE) and many patients with SLE have co-existing APS. To our knowledge no large-scale study has been undertaken to compare cardiac infarct sizes between patients with SLE ± APS and age- and gender-matched controls. Given that patients with SLE have greater cardiovascular risks and increased mortality due to cardiovascular events,[14] it is relevant to investigate if, at the experimental level, IgG from SLE and/or APS enhance cardiac I/R injury. In vivo rat studies have shown that the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)-positive cardiomyocytes in I/R injury can be reduced by treatment with a caspase inhibitor,[15] resulting in a reduced infarct size indicating that apoptosis plays an important role in I/R-induced damage.
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