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

Optimal dose of Domain V in cardiac IRI.(A) C57BL/6 WT mice were treated with control or escalating doses of rhDomain V (n = 7) and assayed for troponin I by ELISA. (B) Mice treated with rhDomain V 40 μM (n = 7) had lower levels of apoptosis compared with control (n = 7). (C) Representative image from within the AAR showing apoptotic cells using the Deadend Fluorometric TUNEL system in a mouse treated with sham LAD ligation, (D) saline and (E) rh Domain V. Images obtained using a Zeiss AxioVert A1 light microscope. DV = Domain V. Points represent number of apoptotic cells in individual mouse cardiac tissue. The horizontal line for each group represents the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152681.g003: Optimal dose of Domain V in cardiac IRI.(A) C57BL/6 WT mice were treated with control or escalating doses of rhDomain V (n = 7) and assayed for troponin I by ELISA. (B) Mice treated with rhDomain V 40 μM (n = 7) had lower levels of apoptosis compared with control (n = 7). (C) Representative image from within the AAR showing apoptotic cells using the Deadend Fluorometric TUNEL system in a mouse treated with sham LAD ligation, (D) saline and (E) rh Domain V. Images obtained using a Zeiss AxioVert A1 light microscope. DV = Domain V. Points represent number of apoptotic cells in individual mouse cardiac tissue. The horizontal line for each group represents the mean.

Mentions: A dose escalation study was performed in a separate group of mice to clarify the optimal dose of rhDomain V for protection from cardiac IRI. Extent of myonecrosis was defined by ultrasensitive troponin I level 24 h after IRI. Domain V or control was delivered after ischemia and prior to reperfusion. It was confirmed that an intravenous dose of 40 μmol/L rhDomain V is the optimal dose over a range of 4–80 μM (Fig 3A). The control and rhDomain V 40 μmol/L groups had cardiac tissue collected for quantitation of apoptotic cells. Domain V treatment resulted in a significant reduction in apoptotic cells compared with control (n = 7) (Fig 3B).


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)

Optimal dose of Domain V in cardiac IRI.(A) C57BL/6 WT mice were treated with control or escalating doses of rhDomain V (n = 7) and assayed for troponin I by ELISA. (B) Mice treated with rhDomain V 40 μM (n = 7) had lower levels of apoptosis compared with control (n = 7). (C) Representative image from within the AAR showing apoptotic cells using the Deadend Fluorometric TUNEL system in a mouse treated with sham LAD ligation, (D) saline and (E) rh Domain V. Images obtained using a Zeiss AxioVert A1 light microscope. DV = Domain V. Points represent number of apoptotic cells in individual mouse cardiac tissue. The horizontal line for each group represents the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152681.g003: Optimal dose of Domain V in cardiac IRI.(A) C57BL/6 WT mice were treated with control or escalating doses of rhDomain V (n = 7) and assayed for troponin I by ELISA. (B) Mice treated with rhDomain V 40 μM (n = 7) had lower levels of apoptosis compared with control (n = 7). (C) Representative image from within the AAR showing apoptotic cells using the Deadend Fluorometric TUNEL system in a mouse treated with sham LAD ligation, (D) saline and (E) rh Domain V. Images obtained using a Zeiss AxioVert A1 light microscope. DV = Domain V. Points represent number of apoptotic cells in individual mouse cardiac tissue. The horizontal line for each group represents the mean.
Mentions: A dose escalation study was performed in a separate group of mice to clarify the optimal dose of rhDomain V for protection from cardiac IRI. Extent of myonecrosis was defined by ultrasensitive troponin I level 24 h after IRI. Domain V or control was delivered after ischemia and prior to reperfusion. It was confirmed that an intravenous dose of 40 μmol/L rhDomain V is the optimal dose over a range of 4–80 μM (Fig 3A). The control and rhDomain V 40 μmol/L groups had cardiac tissue collected for quantitation of apoptotic cells. Domain V treatment resulted in a significant reduction in apoptotic cells compared with control (n = 7) (Fig 3B).

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