期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 2, 页码 439-458出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160530
关键词
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资金
- National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL102101, R01HL125501, 5T32HL066987-13]
- Boston Children's Hospital Research Faculty Council Award for Pilot Study
- Deutsche Akademie der Naturforscher Leopoldina (Nationale Akademie der Wissenschaften)
- German Cardiac Society (Deutsche Gesellschaft fuer Kardiologie)
- Deutsche Forschungsgemeinschaft [CH 1734/1-1]
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.
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