Abstract
Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.
Highlights
The World Health Organization has estimated that 48% of all deaths due to non-communicable disease in 2008 (17 million deaths worldwide) resulted from cardiovascular disease.[1]
This study confirms the hypothesis that rhDomain V protects from cardiac ischemia reperfusion injury’ (IRI) with a 44% reduction in infarction size
The magnitude of protection was not diluted when rhDomain V was delivered at the later time point, a finding with biological plausibility, as reperfusion is required for binding of natural antibodies (NAb) to damaged endothelium
Summary
The World Health Organization has estimated that 48% of all deaths due to non-communicable disease in 2008 (17 million deaths worldwide) resulted from cardiovascular disease.[1]. Natural antibodies are germline encoded and produced primarily by B1 B lymphocytes in the absence of external antigen stimulation.[17] Despite low affinity and restricted epitope specificities they bind to these altered and exposed neoantigens,[14,16,17,18] which results in complement activation, through the lectin pathway.[19] Evidence supporting NAbs amplification of inflammatory tissue injury is derived from studies in antibody deficient recombination activation gene-deficient (Rag-1 -/-) mice These mice are protected from IRI with injury restored through reconstitution by IgM obtained from normal mouse sera.[20,21,22] Based upon these concepts the current paradigm of cardiac IRI comprises intrinsic cellular ischemic injury and an extrinsic inflammatory response initiated by the innate immune system and NAbs. Beta 2 Glycoprotein I (β2GPI) is an abundant 43kDa circulating plasma protein[23] that plays an important role in vascular biology and may provide another link between the innate immune system and tissue injury during IRI. This was deemed necessary in view of the confounding effect of having Domain I available for NAb binding, which can initiate an immune response in its own right
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