Limits...
The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury.

Zhang P, Weaver JC, Chen G, Beretov J, Atsumi T, Qi M, Bhindi R, Qi JC, Madigan MC, Giannakopoulos B, Krilis SA - PLoS ONE (2016)

Bottom Line: 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 V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, Australia.

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.

Show MeSH

Related in: MedlinePlus

Domain V protects from cardiac IRI in Rag-1 -/- antibody deficient mice reconstituted with natural IgM antibodies.(A) Rag-1 -/- mice were treated with saline or pooled murine IgM prior to IRI. The mice treated with IgM were further treated with either saline or rhDomain V at the time of reperfusion. Domain V reduced Troponin I levels at 24 h to similar levels to the antibody deficient mice. (B) Treatment with rhDomain V reduced infarction size (as percentage of total LV) in antibody deficient mice reconstituted with pooled IgM. IgM = murine immunoglobulin M. Individual points represent infarct size as a % of LV of a single mouse. The horizontal line for each study group represents the mean.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4816326&req=5

pone.0152681.g006: Domain V protects from cardiac IRI in Rag-1 -/- antibody deficient mice reconstituted with natural IgM antibodies.(A) Rag-1 -/- mice were treated with saline or pooled murine IgM prior to IRI. The mice treated with IgM were further treated with either saline or rhDomain V at the time of reperfusion. Domain V reduced Troponin I levels at 24 h to similar levels to the antibody deficient mice. (B) Treatment with rhDomain V reduced infarction size (as percentage of total LV) in antibody deficient mice reconstituted with pooled IgM. IgM = murine immunoglobulin M. Individual points represent infarct size as a % of LV of a single mouse. The horizontal line for each study group represents the mean.

Mentions: Rag-1 -/- mice were treated with normal saline or reconstituted with pooled murine IgM (Fig 6). Reconstitution with IgM prior to IRI increased myocardial injury as defined by troponin I level at 24 h (n = 8 per group) (Fig 6A) and infarction size on TTC (Fig 6B). Domain V delivered at the time of reperfusion prevented the IgM induced myocardial injury in Rag-1 -/- mice (Fig 6A and 6B). Treatment with rhDomain V without IgM reconstitution did not further reduce infarction size. There was a good correlation between infarction size on TTC and serum troponin at 24 h (r = 0.806, p < 0.001).


The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury.

Zhang P, Weaver JC, Chen G, Beretov J, Atsumi T, Qi M, Bhindi R, Qi JC, Madigan MC, Giannakopoulos B, Krilis SA - PLoS ONE (2016)

Domain V protects from cardiac IRI in Rag-1 -/- antibody deficient mice reconstituted with natural IgM antibodies.(A) Rag-1 -/- mice were treated with saline or pooled murine IgM prior to IRI. The mice treated with IgM were further treated with either saline or rhDomain V at the time of reperfusion. Domain V reduced Troponin I levels at 24 h to similar levels to the antibody deficient mice. (B) Treatment with rhDomain V reduced infarction size (as percentage of total LV) in antibody deficient mice reconstituted with pooled IgM. IgM = murine immunoglobulin M. Individual points represent infarct size as a % of LV of a single mouse. The horizontal line for each study group represents the mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816326&req=5

pone.0152681.g006: Domain V protects from cardiac IRI in Rag-1 -/- antibody deficient mice reconstituted with natural IgM antibodies.(A) Rag-1 -/- mice were treated with saline or pooled murine IgM prior to IRI. The mice treated with IgM were further treated with either saline or rhDomain V at the time of reperfusion. Domain V reduced Troponin I levels at 24 h to similar levels to the antibody deficient mice. (B) Treatment with rhDomain V reduced infarction size (as percentage of total LV) in antibody deficient mice reconstituted with pooled IgM. IgM = murine immunoglobulin M. Individual points represent infarct size as a % of LV of a single mouse. The horizontal line for each study group represents the mean.
Mentions: Rag-1 -/- mice were treated with normal saline or reconstituted with pooled murine IgM (Fig 6). Reconstitution with IgM prior to IRI increased myocardial injury as defined by troponin I level at 24 h (n = 8 per group) (Fig 6A) and infarction size on TTC (Fig 6B). Domain V delivered at the time of reperfusion prevented the IgM induced myocardial injury in Rag-1 -/- mice (Fig 6A and 6B). Treatment with rhDomain V without IgM reconstitution did not further reduce infarction size. There was a good correlation between infarction size on TTC and serum troponin at 24 h (r = 0.806, p < 0.001).

Bottom Line: 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 V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, Australia.

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.

Show MeSH
Related in: MedlinePlus