VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice

Alexander S. Savchenko, Julian I. Borissoff, Kimberly Martinod, Simon F. De Meyer, Maureen Gallant, Luise Erpenbeck, Alexander Brill, Yanming Wang, Denisa D. Wagner

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Innate immune cells play a major role in the early response to myocardial ischemia/reperfusion (MI/R) injury. Recombinant human ADAMTS13 (rhADAMTS13), cleaving von Willebrand factor (VWF), reduces leukocyte recruitment in mice. Death of cardiomyo-cytes and the possible formation of neutrophil extracellular traps (NETs) may result in chromatin release that is prothrombotic and cytotoxic. We investigated the pathophysi-ological role of extracellular chromatin during MI/R to evaluate the therapeutic potential of targeting extracellular DNA and VWF by using DNase I with/without rhADAMTS13. Finally, we examined the impact of histone citrullination and NETosis by peptidylarginine deiminase 4 (PAD4) on MI/R. We used a 24-hour MI/R mouse surgical model. MI/R injury caused an increase in plasma nucleosomes, abundant neutrophil infiltration, and the presence of citrullinated histone H3 at the site of injury. Both monotherapies and coadministration of DNase I and rhADAMTS13 revealed a cardioprotective effect, resulting in subsequent improvement of cardiac contractile function. PAD4-/- mice, which do not produce NETs, were also significantly protected from MI/R and DNase I treatment had no further beneficial effect. We demonstrate that extra cellular chromatin released through NETosis exacerbates MI/R injury. Targeting both VWF-mediated leukocyte recruitment and chromatin removal may be a new therapeutic strategy to reduce ischemia-related cardiac damage.

Original languageEnglish (US)
Pages (from-to)141-148
Number of pages8
JournalBlood
Volume123
Issue number1
DOIs
StatePublished - Jan 2 2014

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Myocardial Reperfusion Injury
von Willebrand Factor
Reperfusion Injury
Chromatin
Myocardial Ischemia
Deoxyribonuclease I
Leukocytes
Myocardial Reperfusion
Histones
Nucleosomes
Infiltration
Anatomic Models
Neutrophil Infiltration
Plasmas
protein-arginine deiminase
DNA
Ischemia
Wounds and Injuries
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Savchenko, A. S., Borissoff, J. I., Martinod, K., De Meyer, S. F., Gallant, M., Erpenbeck, L., ... Wagner, D. D. (2014). VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood, 123(1), 141-148. https://doi.org/10.1182/blood-2013-07-514992
Savchenko, Alexander S. ; Borissoff, Julian I. ; Martinod, Kimberly ; De Meyer, Simon F. ; Gallant, Maureen ; Erpenbeck, Luise ; Brill, Alexander ; Wang, Yanming ; Wagner, Denisa D. / VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. In: Blood. 2014 ; Vol. 123, No. 1. pp. 141-148.
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Savchenko, AS, Borissoff, JI, Martinod, K, De Meyer, SF, Gallant, M, Erpenbeck, L, Brill, A, Wang, Y & Wagner, DD 2014, 'VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice', Blood, vol. 123, no. 1, pp. 141-148. https://doi.org/10.1182/blood-2013-07-514992

VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. / Savchenko, Alexander S.; Borissoff, Julian I.; Martinod, Kimberly; De Meyer, Simon F.; Gallant, Maureen; Erpenbeck, Luise; Brill, Alexander; Wang, Yanming; Wagner, Denisa D.

In: Blood, Vol. 123, No. 1, 02.01.2014, p. 141-148.

Research output: Contribution to journalArticle

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T1 - VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice

AU - Savchenko, Alexander S.

AU - Borissoff, Julian I.

AU - Martinod, Kimberly

AU - De Meyer, Simon F.

AU - Gallant, Maureen

AU - Erpenbeck, Luise

AU - Brill, Alexander

AU - Wang, Yanming

AU - Wagner, Denisa D.

PY - 2014/1/2

Y1 - 2014/1/2

N2 - Innate immune cells play a major role in the early response to myocardial ischemia/reperfusion (MI/R) injury. Recombinant human ADAMTS13 (rhADAMTS13), cleaving von Willebrand factor (VWF), reduces leukocyte recruitment in mice. Death of cardiomyo-cytes and the possible formation of neutrophil extracellular traps (NETs) may result in chromatin release that is prothrombotic and cytotoxic. We investigated the pathophysi-ological role of extracellular chromatin during MI/R to evaluate the therapeutic potential of targeting extracellular DNA and VWF by using DNase I with/without rhADAMTS13. Finally, we examined the impact of histone citrullination and NETosis by peptidylarginine deiminase 4 (PAD4) on MI/R. We used a 24-hour MI/R mouse surgical model. MI/R injury caused an increase in plasma nucleosomes, abundant neutrophil infiltration, and the presence of citrullinated histone H3 at the site of injury. Both monotherapies and coadministration of DNase I and rhADAMTS13 revealed a cardioprotective effect, resulting in subsequent improvement of cardiac contractile function. PAD4-/- mice, which do not produce NETs, were also significantly protected from MI/R and DNase I treatment had no further beneficial effect. We demonstrate that extra cellular chromatin released through NETosis exacerbates MI/R injury. Targeting both VWF-mediated leukocyte recruitment and chromatin removal may be a new therapeutic strategy to reduce ischemia-related cardiac damage.

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