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The fibrin-derived peptide Bβ15–42 protects the myocardium against ischemia-reperfusion injury

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Abstract

In the event of a myocardial infarction, current interventions aim to reopen the occluded vessel to reduce myocardial damage and injury. Although reperfusion is essential for tissue salvage, it can cause further damage and the onset of inflammation. We show a novel anti-inflammatory effect of a fibrin-derived peptide, Bβ15–42. This peptide competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial (VE)-cadherin, thereby preventing transmigration of leukocytes across endothelial cell monolayers. In acute or chronic rat models of myocardial ischemia-reperfusion injury, Bβ15–42 substantially reduces leukocyte infiltration, infarct size and subsequent scar formation. The pathogenic role of fibrinogen products is further confirmed in fibrinogen knockout mice, in which infarct size was substantially smaller than in wild-type animals. Our findings conclude that the interplay of fibrin fragments, leukocytes and VE-cadherin contribute to the pathogenesis of myocardial damage and reperfusion injury. The naturally occurring peptide Bβ15–42 represents a potential candidate for reperfusion therapy in humans.

NOTE: In the HTML version of this paper originally published online, the name of an author was given incorrectly. The correct name for Peter Fried is Peter Friedl. Also, the first affiliation was given incorrectly. The correct affiliation is Department of General Dermatology, Medical University of Vienna, 18-20 Waehringer Guertel, Vienna, 1090, Austria. These errors have been corrected in the HTML version of the article.

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Figure 1: Fibrin fragments bind to VE-cadherin.
Figure 2: Effects of NDSK-II, NDSK or Bβ15–42 (each 0–200 nM) on (a) adhesion and (b) migration of PBMC across monolayers of HUVEC.
Figure 3: Bβ15–42 reduces leukocyte transmigration.
Figure 4: Determination of infarct size in isolated rat hearts subjected to 20 min of ischemia and 2 h of reperfusion.
Figure 5: Effects of Bβ15–42 during myocardial reperfusion injury.
Figure 6: Determination of infarct size in wild-type and Fgg−/− mice subjected to 20 min of LAD occlusion and 2 h reperfusion.

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  • 23 February 2005

    The HTML version was updated with the correct spelling of Author's name and correct affiliation

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Acknowledgements

This work was supported by research grants from the Austrian Science Foundation (P15099 to P.P.), the Stavros Niarchos foundation (to K.W.) and the Deutsche Forschungsgemeinschaft (Za243/8-1 to K.Z.). We wish to thank the following persons: B. Binder of the Institute of Vascular Biology and Thrombosis Research, School of Medicine, University of Vienna, for providing NDSK; U.M. Losert and the staff of the Biomedical Sciences Center, School of Medicine, University of Vienna. Also A. Treiber, M. Sager and the staff of the Biological Sciences Unit, University Hospital of Dusseldorf.

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Correspondence to Kai Zacharowski.

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Competing interests

Peter Petzelbauer is a founder of a pharmaceutical company (Fibrex Medical R&D), which owns the rights to commercialize peptide Bβ15-42 for therapeutic use. Parts of the surgical equipment have been provided by Fibrex Medical R&D.

Supplementary information

Supplementary Fig. 1

AR of isolated rat hearts subjected to myocardial ischemia/reperfusion. (PDF 43 kb)

Supplementary Fig. 2

AR of rat hearts subjected to acute myocardial ischemia/reperfusion. (PDF 32 kb)

Supplementary Fig. 3

AR of rat hearts subjected to chronic myocardial ischemia/reperfusion. (PDF 81 kb)

Supplementary Fig. 4

AR of mice hearts subjected to acute myocardial ischemia/reperfusion. (PDF 37 kb)

Supplementary Table 1

Effects of Bβ15-42 on clotting parameters in the rat (n = 3/group). (PDF 40 kb)

Supplementary Methods (PDF 126 kb)

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Petzelbauer, P., Zacharowski, P., Miyazaki, Y. et al. The fibrin-derived peptide Bβ15–42 protects the myocardium against ischemia-reperfusion injury. Nat Med 11, 298–304 (2005). https://doi.org/10.1038/nm1198

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