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Research Article

Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury

Wilhelm J. Schwaeble, Nicholas J. Lynch, James E. Clark, Michael Marber, Nilesh J. Samani, Youssif Mohammed Ali, Thomas Dudler, Brian Parent, Karl Lhotta, Russell Wallis, Conrad A. Farrar, Steven Sacks, Haekyung Lee, Ming Zhang, Daisuke Iwaki, Minoru Takahashi, Teizo Fujita, Clark E. Tedford, and Cordula M. Stover
  1. aDepartment of Infection, Immunity, and Inflammation, and
  2. cDepartment of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
  3. bBritish Heart Foundation Centre,
  4. gMedical Research Council Centre for Transplantation, King's College London, London, United Kingdom;
  5. dFaculty of Pharmacy, University of Mansoura, Mansoura, Egypt;
  6. eOmeros Corporation, Seattle, WA;
  7. fLandeskrankenhaus Feldkirch, Feldkirch, Austria;
  8. hDepartment of Anesthesiology, State University of New York-Downstate Medical Center, New York, NY; and
  9. iDepartment of Immunology, Fukushima Medical University, Fukushima, Japan

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PNAS first published April 18, 2011; https://doi.org/10.1073/pnas.1101748108
Wilhelm J. Schwaeble
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  • For correspondence: ws5@le.ac.uk
Nicholas J. Lynch
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James E. Clark
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Michael Marber
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Nilesh J. Samani
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Youssif Mohammed Ali
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Thomas Dudler
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Brian Parent
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Karl Lhotta
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Russell Wallis
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Conrad A. Farrar
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Steven Sacks
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Haekyung Lee
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Ming Zhang
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Daisuke Iwaki
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Minoru Takahashi
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Teizo Fujita
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Clark E. Tedford
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Cordula M. Stover
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  1. Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011)

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Abstract

Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2–deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti–MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.

  • cardiovascular

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: ws5{at}le.ac.uk.
  • Author contributions: W.J.S., N.J.L., J.E.C., M.M., S.S., C.E.T., and C.M.S. designed research; N.J.L., J.E.C., Y.M.A., T.D., B.P., H.L., M.Z., D.I., M.T., T.F., and C.M.S. performed research; T.D., B.P., K.L., R.W., C.A.F., D.I., M.T., T.F., C.E.T., and C.M.S. contributed new reagents/analytic tools; W.J.S., N.J.L., J.E.C., M.M., N.J.S., S.S., and M.Z. analyzed data; and W.J.S., N.J.L., J.E.C., and N.J.S. wrote the paper.

  • Conflict of interest statement: C.E.T., B.P., and T.D. hold shares in Omeros Inc., Seattle, WA, which aims to market recombinant anti–MASP-2 mAb for therapeutic purposes.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1101748108/-/DCSupplemental.

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Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury
Wilhelm J. Schwaeble, Nicholas J. Lynch, James E. Clark, Michael Marber, Nilesh J. Samani, Youssif Mohammed Ali, Thomas Dudler, Brian Parent, Karl Lhotta, Russell Wallis, Conrad A. Farrar, Steven Sacks, Haekyung Lee, Ming Zhang, Daisuke Iwaki, Minoru Takahashi, Teizo Fujita, Clark E. Tedford, Cordula M. Stover
Proceedings of the National Academy of Sciences Apr 2011, 201101748; DOI: 10.1073/pnas.1101748108

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Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury
Wilhelm J. Schwaeble, Nicholas J. Lynch, James E. Clark, Michael Marber, Nilesh J. Samani, Youssif Mohammed Ali, Thomas Dudler, Brian Parent, Karl Lhotta, Russell Wallis, Conrad A. Farrar, Steven Sacks, Haekyung Lee, Ming Zhang, Daisuke Iwaki, Minoru Takahashi, Teizo Fujita, Clark E. Tedford, Cordula M. Stover
Proceedings of the National Academy of Sciences Apr 2011, 201101748; DOI: 10.1073/pnas.1101748108
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