title: VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice.
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 cardiomyocytes and the possible formation of neutrophil extracellular traps (NETs) may result in chromatin release that is prothrombotic and cytotoxic. We investigated the pathophysiological 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 extracellular 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.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Savchenko
authors.forename: Julian I
authors.initials: JI
authors.lastname: Borissoff
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.forename: Luise
authors.initials: L
authors.lastname: Erpenbeck
authors.forename: Alexander
authors.initials: A
authors.lastname: Brill
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D002956:Citrulline / Q000737:chemistry; D003850:Deoxyribonuclease I / Q000378:metabolism; D004452:Echocardiography; D006657:Histones / Q000737:chemistry; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate; D007962:Leukocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D000080002:Protein-Arginine Deiminase Type 4; D011994:Recombinant Proteins / Q000737:chemistry; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D002956:Citrulline; D006867:Hydrolases; D003850:Deoxyribonuclease I; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse