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Cited by 218Neutrophil, Myeloperoxidase and Oxidative MechanismsCardiac Fibrosis and RemodelingInterstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

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Peptidylarginine deiminase 4 promotes age-related organ fibrosis

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Martinod, Kimberly, Witsch, Thilo, Erpenbeck, Luise, Savchenko, Alexander, Hayashi, Hideki, Cherpokova, Deya, Gallant, Maureen, Mauler, Maximilian, Cifuni, Stephen M., Wagner, Denisa D.·2017·Journal of Experimental Medicine
DOI 10.1084/jem.20160530PMC PMC5294849
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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.

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Figure 1. Increased neutrophil and platelet count, formation of platelet–neutrophil complexes, and neutrophil susceptibility to produce NETs in aged C57BL/6NIA mice. (A) Neutrophil counts in peripheral blood of young (2 mo) versus old (20–24 mo) WT mice; n = 16–18. (B) Platelet counts in young (2 mo) versus old (20–24 mo) WT mice; n = 16–18. (C) Quantification by flow cytometry of platelet–neutrophil complexes (CD41+Ly6G+) in whole blood collected from young (2–3 mo) and old (20–24 mo) mice; n = 7–12. (D) Quantification of Ly6G-positive neutrophils in cytospins of the total leukocyte population; n = 6–8. (E) Quantification of the percentage of H3Cit-positive neutrophils by thresholding analysis of immunostained cytospins of RBC-depleted blood cells; n = 6–8. In D and E, young mice were 6–8 wk old and old mice were 15–20 mo old. (F) Percentage of NET-forming peripheral blood neutrophils after incubation with vehicle (unstimulated [US]), 4 µM ionomycin (Iono), or 100 nM PMA for 3.5 h. Neutrophils from old (24–27 mo) mice formed significantly more NETs under all conditions than neutrophils from young (2–5 mo) mice; n = 5. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Student’s t test. The graphs show mean and SEM from 16–18 (A and B), 7–12 (C), 6–8 (D and E), and 5 (F) mice per group from five (A and B), three (C), or two (D–F) independent experiments.
Figure 1. Increased neutrophil and platelet count, formation of platelet–neutrophil complexes, and neutrophil susceptibility to produce NETs in aged C57BL/6NIA mice. (A) Neutrophil counts in peripheral blood of young (2 mo) versus old (20–24 mo) WT mice; n = 16–18. (B) Platelet counts in young (2 mo) versus old (20–24 mo) WT mice; n = 16–18. (C) Quantification by flow cytometry of platelet–neutrophil complexes (CD41+Ly6G+) in whole blood collected from young (2–3 mo) and old (20–24 mo) mice; n = 7–12. (D) Quantification of Ly6G-positive neutrophils in cytospins of the total leukocyte population; n = 6–8. (E) Quantification of the percentage of H3Cit-positive neutrophils by thresholding analysis of immunostained cytospins of RBC-depleted blood cells; n = 6–8. In D and E, young mice were 6–8 wk old and old mice were 15–20 mo old. (F) Percentage of NET-forming peripheral blood neutrophils after incubation with vehicle (unstimulated [US]), 4 µM ionomycin (Iono), or 100 nM PMA for 3.5 h. Neutrophils from old (24–27 mo) mice formed significantly more NETs under all conditions than neutrophils from young (2–5 mo) mice; n = 5. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Student’s t test. The graphs show mean and SEM from 16–18 (A and B), 7–12 (C), 6–8 (D and E), and 5 (F) mice per group from five (A and B), three (C), or two (D–F) independent experiments.CC BY-NC-SA · PubMed Central
Figure 2. Neutrophils and platelets in aging WT or PAD4−/− C57BL/6J mice. (A and B) Neutrophil (A) and platelet (B) counts in peripheral blood of young (2 mo) versus aging (14–17 mo) WT or PAD4−/− mice; n = 12–24. (C) Quantification of Ly6G-positive neutrophils in the total leukocyte population; n = 9–10. (D) Quantification of the percentage of H3Cit-positive neutrophils by thresholding analysis; n = 9–10. (E) Percentage of NET-forming isolated peripheral blood neutrophils after 3.5 h of ex vivo incubation with vehicle (US), 4 µM ionomycin (Iono), or 200 nM PMA for 3.5 h; n = 8. (F) Quantification by flow cytometry of platelet–neutrophil complexes (CD41+Ly6G+) in whole blood; n = 7–12. (G) TGFβ expression on activated platelets was determined by flow cytometric analysis in diluted whole blood stimulated with 10 µM ADP + 3 µM U46619; n = 6–11. Significance was determined by Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001. The graphs show mean and SEM from 12–24 (A and B), 9–10 (C and D), 8 (E), 7–12 (F), or 6–11 (G) mice per group from four (A, B, and F), three (G), or two (C–E) independent experiments.
Figure 2. Neutrophils and platelets in aging WT or PAD4−/− C57BL/6J mice. (A and B) Neutrophil (A) and platelet (B) counts in peripheral blood of young (2 mo) versus aging (14–17 mo) WT or PAD4−/− mice; n = 12–24. (C) Quantification of Ly6G-positive neutrophils in the total leukocyte population; n = 9–10. (D) Quantification of the percentage of H3Cit-positive neutrophils by thresholding analysis; n = 9–10. (E) Percentage of NET-forming isolated peripheral blood neutrophils after 3.5 h of ex vivo incubation with vehicle (US), 4 µM ionomycin (Iono), or 200 nM PMA for 3.5 h; n = 8. (F) Quantification by flow cytometry of platelet–neutrophil complexes (CD41+Ly6G+) in whole blood; n = 7–12. (G) TGFβ expression on activated platelets was determined by flow cytometric analysis in diluted whole blood stimulated with 10 µM ADP + 3 µM U46619; n = 6–11. Significance was determined by Student’s t test. *, P < 0.05; **, P < 0.01; ***, P < 0.001. The graphs show mean and SEM from 12–24 (A and B), 9–10 (C and D), 8 (E), 7–12 (F), or 6–11 (G) mice per group from four (A, B, and F), three (G), or two (C–E) independent experiments.CC BY-NC-SA · PubMed Central
Figure 3. PAD4−/− mice are protected from age-related decline in systolic and diastolic heart function compared with WT mice. (A and B) LVEF, as a measure of systolic function, and cardiac dimensions (IVS;d, LVPW;d, and LVID;d) of WT and PAD4−/− retired breeders (12–17 mo) were measured by transthoracic echocardiography. (A) Representative ultrasound M-mode images of the left ventricle in an old PAD4−/− mouse compared with an old WT mouse. D, diastole; S, systole. (B) Quantification of LVEF (left) and cardiac dimensions (right panels) in WT and PAD4−/− retired breeders; n = 7–11. (C) The same echocardiographic measurements of LVEF (left) and cardiac dimensions (right) were repeated in a group of young (6–8 wk) and old (14–18 mo) WT and PAD4−/− mice that had been kept on standard laboratory diet; n = 4–7. (D and E) Ventricular diastolic dysfunction was evaluated in young WT and PAD4−/− (6–8 wk) mice as well as old WT and PAD4−/− mice (15–20 mo). The flow pattern across the mitral valve was assessed using pulsed wave Doppler mode, and the ventricular filling pattern was calculated as the ratio between the E and A wave. (D) Characteristic images of pulsed wave Doppler measurements of the E and A wave showed a normal E/A pattern (E > A) in the old PAD4−/− mice and a reversed pattern (E < A) in the old WT mice (A was taller than E), leading to a ratio of <1. (E) Quantification of the E/A ratio in young and old WT and PAD4−/− mice. An E/A ratio <1 is evidence of impaired ventricular relaxation; n = 4–6. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Mann–Whitney U test. The graphs show mean and SEM from 7–11 (A and B), 4–7 (C), and 4–6 (D and E) mice per group from four (A and B) or two (C–E) independent experiments.
Figure 3. PAD4−/− mice are protected from age-related decline in systolic and diastolic heart function compared with WT mice. (A and B) LVEF, as a measure of systolic function, and cardiac dimensions (IVS;d, LVPW;d, and LVID;d) of WT and PAD4−/− retired breeders (12–17 mo) were measured by transthoracic echocardiography. (A) Representative ultrasound M-mode images of the left ventricle in an old PAD4−/− mouse compared with an old WT mouse. D, diastole; S, systole. (B) Quantification of LVEF (left) and cardiac dimensions (right panels) in WT and PAD4−/− retired breeders; n = 7–11. (C) The same echocardiographic measurements of LVEF (left) and cardiac dimensions (right) were repeated in a group of young (6–8 wk) and old (14–18 mo) WT and PAD4−/− mice that had been kept on standard laboratory diet; n = 4–7. (D and E) Ventricular diastolic dysfunction was evaluated in young WT and PAD4−/− (6–8 wk) mice as well as old WT and PAD4−/− mice (15–20 mo). The flow pattern across the mitral valve was assessed using pulsed wave Doppler mode, and the ventricular filling pattern was calculated as the ratio between the E and A wave. (D) Characteristic images of pulsed wave Doppler measurements of the E and A wave showed a normal E/A pattern (E > A) in the old PAD4−/− mice and a reversed pattern (E < A) in the old WT mice (A was taller than E), leading to a ratio of <1. (E) Quantification of the E/A ratio in young and old WT and PAD4−/− mice. An E/A ratio <1 is evidence of impaired ventricular relaxation; n = 4–6. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Mann–Whitney U test. The graphs show mean and SEM from 7–11 (A and B), 4–7 (C), and 4–6 (D and E) mice per group from four (A and B) or two (C–E) independent experiments.CC BY-NC-SA · PubMed Central
Figure 4. PAD4 deficiency reduces age-related cardiac fibrosis. (A) Cardiac interstitial fibrosis was assessed by Sirius red staining for collagen fibers in sections of the left ventricle of the heart of WT and PAD4−/− retired breeders (12–17 mo). The percentage of fibrotic (red) area in the heart tissue was quantified by ImageJ, excluding perivascular fibrosis. In PAD4−/− retired breeders, there was significantly less interstitial fibrosis than in WT retired breeders; n = 6. (B) The same analysis was performed for young (6–8 wk) WT and young PAD4−/− mice as well as for old (14–18 mo) WT and old PAD4−/− mice on standard diet. Quantification of Sirius red staining again showed less fibrosis in the old PAD4−/− mice compared with the old WT mice. In old PAD4−/− mice, the percentage of interstitial collagen remained comparable with young PAD4−/− mice; n = 7–8. (C and D) Representative Sirius red (left; collagen fibers are red) and Masson’s trichrome (right; collagen fibers are blue) staining in young (C) and old (D) WT or PAD4−/− mice. Arrowheads point to interstitial collagen fibers. (E) Representative immunofluorescent staining for type I collagen in old WT or PAD4−/− mouse hearts. Bars: (C and D) 100 µm; (E) 10 µm. (F) Correlation analysis including all experimental groups between the degree of fibrosis (%) as determined by Sirius red staining, and ejection fraction (EF; %; Spearman r coefficient = −0.42, P = 0.014). *, P < 0.05; **, P < 0.01 by Mann–Whitney U test (A and B) or nonparametric correlation analysis (F). The graphs show mean and SEM from six (A, C, and D), seven to eight (B), or four (E) mice per group from two independent experiments. F shows a correlation analysis of all experimental groups from A and B.
Figure 4. PAD4 deficiency reduces age-related cardiac fibrosis. (A) Cardiac interstitial fibrosis was assessed by Sirius red staining for collagen fibers in sections of the left ventricle of the heart of WT and PAD4−/− retired breeders (12–17 mo). The percentage of fibrotic (red) area in the heart tissue was quantified by ImageJ, excluding perivascular fibrosis. In PAD4−/− retired breeders, there was significantly less interstitial fibrosis than in WT retired breeders; n = 6. (B) The same analysis was performed for young (6–8 wk) WT and young PAD4−/− mice as well as for old (14–18 mo) WT and old PAD4−/− mice on standard diet. Quantification of Sirius red staining again showed less fibrosis in the old PAD4−/− mice compared with the old WT mice. In old PAD4−/− mice, the percentage of interstitial collagen remained comparable with young PAD4−/− mice; n = 7–8. (C and D) Representative Sirius red (left; collagen fibers are red) and Masson’s trichrome (right; collagen fibers are blue) staining in young (C) and old (D) WT or PAD4−/− mice. Arrowheads point to interstitial collagen fibers. (E) Representative immunofluorescent staining for type I collagen in old WT or PAD4−/− mouse hearts. Bars: (C and D) 100 µm; (E) 10 µm. (F) Correlation analysis including all experimental groups between the degree of fibrosis (%) as determined by Sirius red staining, and ejection fraction (EF; %; Spearman r coefficient = −0.42, P = 0.014). *, P < 0.05; **, P < 0.01 by Mann–Whitney U test (A and B) or nonparametric correlation analysis (F). The graphs show mean and SEM from six (A, C, and D), seven to eight (B), or four (E) mice per group from two independent experiments. F shows a correlation analysis of all experimental groups from A and B.CC BY-NC-SA · PubMed Central
Figure 5. Old PAD4−/− mice have significantly less collagen staining in their lungs than old WT mice. (A) The percentage of collagen-positive area in lung tissue of WT and PAD4−/− retired breeders (12–17 mo) was quantified using Masson’s trichrome stain for collagen and subsequently color gating for blue fibers; n = 6–7. (B) Measurement of hydroxyproline content in the right lung was performed; n = 5–9. (C) The same analysis as in A for collagen fibers within the lung tissue was performed for young (6–8 wk) WT and PAD4−/− mice and old (14–18 mo) WT and PAD4−/− mice; n = 4. (D) Representative photographs of lung sections stained with Masson’s trichrome stain are shown. Bar, 20 µm. *, P < 0.05; **, P < 0.01; ****, P < 0.0001 by Mann–Whitney U test. The graphs show mean and SEM from six to seven (A), five to nine (B), or four (C and D) mice per group from three (A), one (B), or two (C and D) independent experiments.
Figure 5. Old PAD4−/− mice have significantly less collagen staining in their lungs than old WT mice. (A) The percentage of collagen-positive area in lung tissue of WT and PAD4−/− retired breeders (12–17 mo) was quantified using Masson’s trichrome stain for collagen and subsequently color gating for blue fibers; n = 6–7. (B) Measurement of hydroxyproline content in the right lung was performed; n = 5–9. (C) The same analysis as in A for collagen fibers within the lung tissue was performed for young (6–8 wk) WT and PAD4−/− mice and old (14–18 mo) WT and PAD4−/− mice; n = 4. (D) Representative photographs of lung sections stained with Masson’s trichrome stain are shown. Bar, 20 µm. *, P < 0.05; **, P < 0.01; ****, P < 0.0001 by Mann–Whitney U test. The graphs show mean and SEM from six to seven (A), five to nine (B), or four (C and D) mice per group from three (A), one (B), or two (C and D) independent experiments.CC BY-NC-SA · PubMed Central
Figure 6. Cardiac and lung tissue have low PAD4 mRNA expression compared with other organs in young and old mice. (A) Quantitative real-time RT-PCR analysis was performed for PAD4 mRNA expression in various tissue types from WT mice. Fold expression was calculated with actin B and hypoxanthine-guanine phosphoribosyltransferase (hprt) as reference genes and normalized to PAD4−/− bone marrow; n = 5. (B) PCR product size and specificity after amplification was verified by conventional PCR on an agarose gel. A representative photograph is shown. (C) Quantitative real-time PCR analysis of PAD4 mRNA expression in young (2 mo) compared with old (20–25 mo) WT C57BL/6NIA mice. Fold expression was calculated with gapdh and hprt as reference genes and normalized to PAD4−/− bone marrow; n = 5. *, P < 0.05 by Student’s t test. The graphs show mean and SEM from five (A and C) or three (B) mice per group from two independent experiments.
Figure 6. Cardiac and lung tissue have low PAD4 mRNA expression compared with other organs in young and old mice. (A) Quantitative real-time RT-PCR analysis was performed for PAD4 mRNA expression in various tissue types from WT mice. Fold expression was calculated with actin B and hypoxanthine-guanine phosphoribosyltransferase (hprt) as reference genes and normalized to PAD4−/− bone marrow; n = 5. (B) PCR product size and specificity after amplification was verified by conventional PCR on an agarose gel. A representative photograph is shown. (C) Quantitative real-time PCR analysis of PAD4 mRNA expression in young (2 mo) compared with old (20–25 mo) WT C57BL/6NIA mice. Fold expression was calculated with gapdh and hprt as reference genes and normalized to PAD4−/− bone marrow; n = 5. *, P < 0.05 by Student’s t test. The graphs show mean and SEM from five (A and C) or three (B) mice per group from two independent experiments.CC BY-NC-SA · PubMed Central
Figure 7. NETosis occurs in the pressure-overload mouse model of cardiac fibrosis. WT or PAD4−/− mice were subjected to AAC or to sham surgery, and 1 d later, cellular composition of the left ventricle was analyzed by flow cytometry. (A and B) Neutrophils were identified as CD45.2+CD11b+Ly6G+ cells (A), and neutrophils undergoing NETosis were identified within this gated population as H3Cit+ (B); n = 3–7. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Student’s t test. (C) Representative immunofluorescence staining images. NETs (arrows) and hypercitrullinated histone H3 (H3Cit)–positive neutrophils (asterisks) were present in WT but not PAD4−/− hearts 1 d after AAC. Bars, 10 µm. The graphs show mean and SEM from three to seven mice per group in two independent experiments.
Figure 7. NETosis occurs in the pressure-overload mouse model of cardiac fibrosis. WT or PAD4−/− mice were subjected to AAC or to sham surgery, and 1 d later, cellular composition of the left ventricle was analyzed by flow cytometry. (A and B) Neutrophils were identified as CD45.2+CD11b+Ly6G+ cells (A), and neutrophils undergoing NETosis were identified within this gated population as H3Cit+ (B); n = 3–7. *, P < 0.05; **, P < 0.01; ***, P < 0.001 by Student’s t test. (C) Representative immunofluorescence staining images. NETs (arrows) and hypercitrullinated histone H3 (H3Cit)–positive neutrophils (asterisks) were present in WT but not PAD4−/− hearts 1 d after AAC. Bars, 10 µm. The graphs show mean and SEM from three to seven mice per group in two independent experiments.CC BY-NC-SA · PubMed Central
Figure 8. Platelet aggregates form within AAC hearts to a greater extent in WT than PAD4−/− mice. (A) Quantification of platelet aggregates (CD41-positive staining) in mice subjected to AAC or a sham operation and perfused immediately after euthanasia. Five fields of view were imaged and analyzed per heart section using a 10× objective; n = 3–7. *, P < 0.05; **, P < 0.01 by Student’s t test. (B) The top panel shows a representative image of sham-operated WT mouse heart immunostained with anti-CD41 antibody to identify platelets. The middle and bottom panels show representative images of the relative presence of CD41+ platelet aggregates (arrows) in WT hearts compared with PAD4−/− hearts. Bars, 10 µm. The graph shows mean and SEM from three to seven mice per group in two independent experiments.
Figure 8. Platelet aggregates form within AAC hearts to a greater extent in WT than PAD4−/− mice. (A) Quantification of platelet aggregates (CD41-positive staining) in mice subjected to AAC or a sham operation and perfused immediately after euthanasia. Five fields of view were imaged and analyzed per heart section using a 10× objective; n = 3–7. *, P < 0.05; **, P < 0.01 by Student’s t test. (B) The top panel shows a representative image of sham-operated WT mouse heart immunostained with anti-CD41 antibody to identify platelets. The middle and bottom panels show representative images of the relative presence of CD41+ platelet aggregates (arrows) in WT hearts compared with PAD4−/− hearts. Bars, 10 µm. The graph shows mean and SEM from three to seven mice per group in two independent experiments.CC BY-NC-SA · PubMed Central
Figure 9. Extracellular DNA/PAD4 contribute to cardiac damage in the pressure-overloaded heart. WT and PAD4−/− mice were subjected to AAC and underwent echocardiography 3, 7, or 28 d after surgery. Mice received either vehicle or rhDNase 1 administration every 12 h for the first 7 d. (A) LVEF measurements in WT, PAD4−/−, or rhDNase 1–treated mice. Range of ejection fraction values (n = 4) from sham-operated animals at each respective time point are shown in gray. The structural parameters IVS;d (B), LVPW;d (C), and LVID;d (D) were similar between all groups. (E–G) Mice were euthanized 28 d after AAC induction for fibrosis analysis. (E) Representative composite images (top) or high magnification (bottom) of the left ventricle stained with Masson’s trichrome. Bar, 100 µm. (F) Quantification of interstitial fibrosis in images of Sirius red–stained heart tissue; n = 6–11. The range of values for percentage of collagen in sham-operated animals is represented by the gray-shaded area. (G) Perivascular fibrosis, quantified as the ratio of collagen-positive area to total vessel area. At least eight vessels were quantified per mouse; n = 6–11. *, P < 0.05; **, P < 0.01 by Student’s t test. The graphs show mean and SEM from n = 4–11 mice per group from three independent experiments.
Figure 9. Extracellular DNA/PAD4 contribute to cardiac damage in the pressure-overloaded heart. WT and PAD4−/− mice were subjected to AAC and underwent echocardiography 3, 7, or 28 d after surgery. Mice received either vehicle or rhDNase 1 administration every 12 h for the first 7 d. (A) LVEF measurements in WT, PAD4−/−, or rhDNase 1–treated mice. Range of ejection fraction values (n = 4) from sham-operated animals at each respective time point are shown in gray. The structural parameters IVS;d (B), LVPW;d (C), and LVID;d (D) were similar between all groups. (E–G) Mice were euthanized 28 d after AAC induction for fibrosis analysis. (E) Representative composite images (top) or high magnification (bottom) of the left ventricle stained with Masson’s trichrome. Bar, 100 µm. (F) Quantification of interstitial fibrosis in images of Sirius red–stained heart tissue; n = 6–11. The range of values for percentage of collagen in sham-operated animals is represented by the gray-shaded area. (G) Perivascular fibrosis, quantified as the ratio of collagen-positive area to total vessel area. At least eight vessels were quantified per mouse; n = 6–11. *, P < 0.05; **, P < 0.01 by Student’s t test. The graphs show mean and SEM from n = 4–11 mice per group from three independent experiments.CC BY-NC-SA · PubMed Central

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Authors
Martinod, K., Witsch, T., Erpenbeck, L., Savchenko, A., Hayashi, H., Cherpokova, D., Gallant, M., Mauler, M., Cifuni, S. M., & Wagner, D. D.
Affiliations
  • Boston Children's Hospital (US)
  • University of Freiburg (DE)
Corresponding author
Wagner, Denisa D.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2016-12-28
Volume
214
Issue
2
Pages
439-458
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20160530
PMC
PMC5294849
OpenAlex
W2562661149
Cited by
218
References
91
Citations by year
2026: 14 · 2025: 23 · 2024: 36 · 2023: 28 · 2022: 20 · 2021: 25 · 2020: 22 · 2019: 21 · 2018: 19 · 2017: 10
FWCI
10.11
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • GRO (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL102101, R01HL125501, 5T32HL066987-13)
  • Boston Children’s Hospital
  • Deutsche Forschungsgemeinschaft (CH 1734/1-1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Keywords
PAD4, neutrophil extracellular traps, NETosis, myocardial fibrosis, pulmonary fibrosis, aging, inflammation, DNase1, platelet recruitment, pressure overload, collagen deposition, cardiac function
MeSH terms
Protein-Arginine Deiminase Type 4, Age Factors, Animals, Collagen, Fibrosis, Hydrolases, Mice, Inbred C57BL, Myocardium, Pulmonary Fibrosis, Ventricular Function, Left, Reactive Oxygen Species, Mice, Extracellular Traps

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