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J Exp Med. 2017 Feb;214(2):439-458. doi: 10.1084/jem.20160530. Epub 2016 Dec 28.

Peptidylarginine deiminase 4 promotes age-related organ fibrosis.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
2
Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
3
Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany.
4
Department of Cardiology and Angiology I, Heart Center, University of Freiburg, 79106 Freiburg, Germany.
5
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 denisa.wagner@childrens.harvard.edu.
6
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115.

Abstract

Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/- mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/- mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/- myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.

PMID:
28031479
PMCID:
PMC5294849
DOI:
10.1084/jem.20160530
[Indexed for MEDLINE]
Free PMC Article

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