Peptidylarginine deiminase 4 promotes age-related organ fibrosis

Journal of Experimental Medicine

Volumn 214, Issue 2, 2017, Pages 439-458

  Martinod, Kimberly ^a,b   Witsch, Thilo ^a,b   Erpenbeck, Luise ^a,b   Savchenko, Alexander ^a,b   Hayashi, Hideki ^a,b   Cherpokova, Deya ^a,b   Gallant, Maureen ^a   Mauler, Maximilian ^c   Cifuni, Stephen M ^a   Wagner, Denisa D ^a,b  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF FREIBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

DEOXYRIBONUCLEASE I; HISTONE H3; PEPTIDYLARGININE DEIMINASE 4; PROTEIN ARGININE DEIMINASE; UNCLASSIFIED DRUG; COLLAGEN; HYDROLASE; PEPTIDYLARGININE DEIMINASE 4, MOUSE; REACTIVE OXYGEN METABOLITE;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BLOOD OXYGEN TENSION; CARDIAC MUSCLE; CONTROLLED STUDY; ECHOCARDIOGRAPHY; EXTRACELLULAR TRAP; FIBROSING ALVEOLITIS; HEART FUNCTION; HEART INJURY; HEART MUSCLE CONTRACTILITY; HEART MUSCLE FIBROSIS; HEART SIZE; HEART TISSUE; IN VITRO STUDY; LUNG FIBROSIS; LUNG PARENCHYMA; MALE; MOUSE; NEUTROPHIL; NEUTROPHIL COUNT; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; AGE; ANIMAL; C57BL MOUSE; FIBROSIS; GENETICS; HEART LEFT VENTRICLE FUNCTION; METABOLISM; PATHOLOGY; PHYSIOLOGY; PULMONARY FIBROSIS;

AGE FACTORS; ANIMALS; COLLAGEN; EXTRACELLULAR TRAPS; FIBROSIS; HYDROLASES; MICE; MICE, INBRED C57BL; MYOCARDIUM; PULMONARY FIBROSIS; REACTIVE OXYGEN SPECIES; VENTRICULAR FUNCTION, LEFT;

EID: 85012306028     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20160530     Document Type: Article

References (87)

1. Afonso, A.S., K.M. Verhamme, M.C. Sturkenboom, and G.G. Brusselle. 2011. COPD in the general population: prevalence, incidence and survival. Respir. Med. 105:1872-1884. http://dx.doi.org/10.1016/j.rmed.2011.06.012
2. Ammarguellat, F., I. Larouche, and E.L. Schiffrin. 2001. Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ETA receptor antagonism. Circulation. 103:319-324. http://dx.doi.org/10.1161/01.CIR.103.2.319
3. Asaga, H., K. Nakashima, T. Senshu, A. Ishigami, and M. Yamada. 2001. Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. J. Leukoc. Biol. 70:46-51.
4. Aw, D., A.B. Silva, and D.B. Palmer. 2007. Immunosenescence: emerging challenges for an ageing population. Immunology. 120:435-446. http://dx.doi.org/10.1111/j.1365-2567.2007.02555.x
5. Azevedo, E.P., A.B. Guimaraes-Costa, G.S. Torezani, C.A. Braga, F.L. Palhano, J.W. Kelly, E.M. Saraiva, and D. Foguel. 2012. Amyloid fibrils trigger the release of neutrophil extracellular traps (NETs), causing fibril fragmentation by NET-associated elastase. J. Biol. Chem. 287:37206-37218. http://dx.doi.org/10.1074/jbc.M112.369942
6. Bancroft, J., and M. Gamble. 2008. Connective tissue and stains. In Theory and Practice of Histological Techniques. J. Bancroft, editor. Churchill-Livingston Elsevier, London. pp. 135-160.
7. Beerman, I., D. Bhattacharya, S. Zandi, M. Sigvardsson, I.L. Weissman, D. Bryder, and D.J. Rossi. 2010. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl. Acad. Sci. USA. 107:5465-5470. http://dx.doi.org/10.1073/pnas.1000834107
8. Bengtsson, T., and M. Lindstrom. 2003. Airborne infectious diseases during infancy and mortality in later life in southern Sweden, 1766-1894. Int. J. Epidemiol. 32:286-294. http://dx.doi.org/10.1093/ije/dyg061
9. Biernacka, A., and N.G. Frangogiannis. 2011. Aging and cardiac fibrosis. Aging Dis. 2:158-173.
10. Borissoff, J.I., I.A. Joosen, M.O. Versteylen, A. Brill, T.A. Fuchs, A.S. Savchenko, M. Gallant, K. Martinod, H. Ten Cate, L. Hofstra, et al. 2013. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler. Thromb. Vasc. Biol. 33:2032-2040. http://dx.doi.org/10.1161/ATV BAHA.113.301627
11. Brill, A., T.A. Fuchs, A.S. Savchenko, G.M. Thomas, K. Martinod, S.F. De Meyer, A.A. Bhandari, and D.D. Wagner. 2012. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10:136-144. http://dx.doi.org/10.1111/j.1538-7836.2011.04544.x
12. Brinkmann, V., U. Reichard, C. Goosmann, B. Fauler, Y. Uhlemann, D.S. Weiss, Y. Weinrauch, and A. Zychlinsky. 2004. Neutrophil extracellular traps kill bacteria. Science. 303:1532-1535. http://dx.doi.org/10.1126/science.1092385
13. Cakman, I., J. Rohwer, R.M. Schutz, H. Kirchner, and L. Rink. 1996. Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mech. Ageing Dev. 87:197-209. http://dx.doi.org/10.1016/0047-6374(96)01708-3
14. Caudrillier, A., K. Kessenbrock, B.M. Gilliss, J.X. Nguyen, M.B. Marques, M. Monestier, P. Toy, Z. Werb, and M.R. Looney. 2012. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122:2661-2671. http://dx.doi.org/10.1172/JCI61303
15. Chang, X., and J. Han. 2006. Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol. Carcinog. 45:183-196. http://dx.doi.org/10.1002/mc.20169
16. Chrysanthopoulou, A., I. Mitroulis, E. Apostolidou, S. Arelaki, D. Mikroulis, T. Konstantinidis, E. Sivridis, M. Koffa, A. Giatromanolaki, D.T. Boumpas, et al. 2014. Neutrophil extracellular traps promote differentiation and function of fibroblasts. J. Pathol. 233:294-307. http://dx.doi.org/10.1002/path.4359
17. Chua, F., S.E. Dunsmore, P.H. Clingen, S.E. Mutsaers, S.D. Shapiro, A.W. Segal, J. Roes, and G.J. Laurent. 2007. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 170:65-74. http://dx.doi.org/10.2353/ajpath.2007.060352
18. Clark, R.A. 1999. Activation of the neutrophil respiratory burst oxidase. J. Infect. Dis. 179(s2):S309-S317. http://dx.doi.org/10.1086/513849
19. Clark, S.R., A.C. Ma, S.A. Tavener, B. McDonald, Z. Goodarzi, M.M. Kelly, K.D. Patel, S. Chakrabarti, E. McAvoy, G.D. Sinclair, et al. 2007. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13:463-469. http://dx.doi.org/10.1038/nm1565
20. Cools-Lartigue, J., J. Spicer, B. McDonald, S. Gowing, S. Chow, B. Giannias, F. Bourdeau, P. Kubes, and L. Ferri. 2013. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123:3446-3458. http://dx.doi.org/10.1172/JCI67484
21. Dai, D.F., and P.S. Rabinovitch. 2009. Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. Trends Cardiovasc. Med. 19:213-220. http://dx.doi.org/10.1016/j.tcm.2009.12.004
22. Dai, Z., T. Aoki, Y. Fukumoto, and H. Shimokawa. 2012. Coronary perivascular fibrosis is associated with impairment of coronary blood flow in patients with non-ischemic heart failure. J. Cardiol. 60:416-421. http://dx.doi.org/10.1016/j.jjcc.2012.06.009
23. DeFrances, C.J., K.A. Cullen, and L.J. Kozak. 2007. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat. 13. Dec:1-209.
24. Demers, M., and D.D. Wagner. 2013. Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression. OncoImmunology. 2:e22946. http://dx.doi.org/10.4161/onci.22946
25. Demers, M., D.S. Krause, D. Schatzberg, K. Martinod, J.R. Voorhees, T.A. Fuchs, D.T. Scadden, and D.D. Wagner. 2012. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancerassociated thrombosis. Proc. Natl. Acad. Sci. USA. 109:13076-13081. http://dx.doi.org/10.1073/pnas.1200419109
26. De Meyer, S.F., G.L. Suidan, T.A. Fuchs, M. Monestier, and D.D. Wagner. 2012. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler. Thromb. Vasc. Biol. 32:1884-1891. http://dx.doi.org/10.1161/ATV BAHA.112.250993
27. Diaz, J.A., T.A. Fuchs, T.O. Jackson, J.A. Kremer Hovinga, B. Lämmle, P.K. Henke, D.D. Myers Jr., D.D. Wagner, and T.W. Wakefield. Michigan Research Venous Group. 2013. Plasma DNA is elevated in patients with deep vein thrombosis. J. Vasc. Surg. Venous Lymphat. Disord. 1:341-348. http://dx.doi.org/10.1016/j.jvsv.2012.12.002
28. Dwivedi, N., J. Upadhyay, I. Neeli, S. Khan, D. Pattanaik, L. Myers, K.A. Kirou, B. Hellmich, B. Knuckley, P.R. Thompson, et al. 2012. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheum. 64:982-992. http://dx.doi.org/10.1002/art.33432
29. Etulain, J., K. Martinod, S.L. Wong, S.M. Cifuni, M. Schattner, and D.D. Wagner. 2015. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 126:242-246. http://dx.doi.org/10.1182/blood-2015-01-624023
30. Finch, C.E., and E.M. Crimmins. 2004. Inflammatory exposure and historical changes in human life-spans. Science. 305:1736-1739. http://dx.doi.org/10.1126/science.1092556
31. Fuchs, T.A., A. Brill, D. Duerschmied, D. Schatzberg, M. Monestier, D.D. Myers Jr., S.K. Wrobleski, T.W. Wakefield, J.H. Hartwig, and D.D. Wagner. 2010. Extracellular DNA traps promote thrombosis. Proc. Natl. Acad. Sci. USA. 107:15880-15885. http://dx.doi.org/10.1073/pnas.1005743107
32. Fuchs, T.A., A. Brill, and D.D. Wagner. 2012. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler. Thromb. Vasc. Biol. 32:1777-1783. http://dx.doi.org/10.1161/ATV BAHA.111.242859
33. Gavillet, M., K. Martinod, R. Renella, C. Harris, N.I. Shapiro, D.D. Wagner, and D.A. Williams. 2015. Flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples. Am. J. Hematol. 90:1155-1158. http://dx.doi.org/10.1002/ajh.24185
34. Gazoti Debessa, C.R., L.B. Mesiano Maifrino, and R. Rodrigues de Souza. 2001. Age related changes of the collagen network of the human heart. Mech. Ageing Dev. 122:1049-1058. http://dx.doi.org/10.1016/S0047-6374(01)00238-X
35. Hakkim, A., B.G. Furnrohr, K. Amann, B. Laube, U.A. Abed, V. Brinkmann, M. Herrmann, R.E. Voll, and A. Zychlinsky. 2010. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl. Acad. Sci. USA. 107:9813-9818. http://dx.doi.org/10.1073/pnas.0909927107
36. Higashiyama, H., M. Sugai, H. Inoue, K. Mizuyachi, H. Kushida, S. Asano, and M. Kinoshita. 2007. Histopathological study of time course changes in inter-renal aortic banding-induced left ventricular hypertrophy of mice. Int. J. Exp. Pathol. 88:31-38. http://dx.doi.org/10.1111/j.1365-2613.2006.00514.x
37. Hilgendorf, I., L.M. Gerhardt, T.C. Tan, C. Winter, T.A. Holderried, B.G. Chousterman, Y. Iwamoto, R. Liao, A. Zirlik, M. Scherer-Crosbie, et al. 2014. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ. Res. 114:1611-1622. http://dx.doi.org/10.1161/CIR CRE SAHA.114.303204
38. Junqueira, L.C., G. Bignolas, and R.R. Brentani. 1979. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem. J. 11:447-455. http://dx.doi.org/10.1007/BF01002772
39. Kessenbrock, K., M. Krumbholz, U. Schonermarck, W. Back, W.L. Gross, Z. Werb, H.J. Grone, V. Brinkmann, and D.E. Jenne. 2009. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15:623-625. http://dx.doi.org/10.1038/nm.1959
40. Kolaczkowska, E., and P. Kubes. 2013. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13:159-175. http://dx.doi.org/10.1038/nri3399
41. Kolaczkowska, E., C.N. Jenne, B.G. Surewaard, A. Thanabalasuriar, W.Y. Lee, M.J. Sanz, K. Mowen, G. Opdenakker, and P. Kubes. 2015. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat. Commun. 6:6673. http://dx.doi.org/10.1038/ncomms7673
42. Kumamoto, T., Y. Kawai, K. Arakawa, N. Morikawa, J. Kuribara, H. Tada, K. Taniguchi, R. Tatami, I. Miyamori, Y. Kominato, et al. 2006. Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients. Eur. Heart J. 27:2081-2087. http://dx.doi.org/10.1093/eurheartj/ehl177
43. Li, P., H. Yao, Z. Zhang, M. Li, Y. Luo, P.R. Thompson, D.S. Gilmour, and Y. Wang. 2008. Regulation of p53 target gene expression by peptidylarginine deiminase 4. Mol. Cell. Biol. 28:4745-4758. http://dx.doi.org/10.1128/MCB.01747-07
44. Loffredo, F.S., A.P. Nikolova, J.R. Pancoast, and R.T. Lee. 2014. Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ. Res. 115:97-107. http://dx.doi.org/10.1161/CIR CRE SAHA.115.302929
45. Lorell, B.H., and B.A. Carabello. 2000. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 102:470-479. http://dx.doi.org/10.1161/01.CIR.102.4.470
46. Martinod, K., and D.D. Wagner. 2014. Thrombosis: tangled up in NETs. Blood. 123:2768-2776. http://dx.doi.org/10.1182/blood-2013-10-463646
47. Martinod, K., M. Demers, T.A. Fuchs, S.L. Wong, A. Brill, M. Gallant, J. Hu, Y. Wang, and D.D. Wagner. 2013. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc. Natl. Acad. Sci. USA. 110:8674-8679. http://dx.doi.org/10.1073/pnas.1301059110
48. Meyer, A., W. Wang, J. Qu, L. Croft, J.L. Degen, B.S. Coller, and J. Ahamed. 2012. Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood. 119:1064-1074. http://dx.doi.org/10.1182/blood-2011-09-377648
49. Meyer, K.C., N.S. Rosenthal, P. Soergel, and K. Peterson. 1998. Neutrophils and low-grade inflammation in the seemingly normal aging human lung. Mech. Ageing Dev. 104:169-181. http://dx.doi.org/10.1016/S0047-6374(98)00065-7
50. Namba, T., H. Tsutsui, H. Tagawa, M. Takahashi, K. Saito, T. Kozai, M. Usui, K. Imanaka-Yoshida, T. Imaizumi, and A. Takeshita. 1997. Regulation of fibrillar collagen gene expression and protein accumulation in volumeoverloaded cardiac hypertrophy. Circulation. 95:2448-2454. http://dx.doi.org/10.1161/01.CIR.95.10.2448
51. National Institute on Aging. 2011. Why Population Aging Matters to Health: A Global Perspective. National Institutes of Health. Available at: https://www.nia.nih.gov/research/publication/global-health-and-aging/overview (accessed November, 2014).
52. Navaratnam, V., K.M. Fleming, J. West, C.J. Smith, R.G. Jenkins, A. Fogarty, and R.B. Hubbard. 2011. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 66:462-467. http://dx.doi.org/10.1136/thx.2010.148031
53. Ogawa, K., K. Suzuki, M. Okutsu, K. Yamazaki, and S. Shinkai. 2008. The association of elevated reactive oxygen species levels from neutrophils with low-grade inflammation in the elderly. Immun. Ageing. 5:13. http://dx.doi.org/10.1186/1742-4933-5-13
54. Parker, H., M. Dragunow, M.B. Hampton, A.J. Kettle, and C.C. Winterbourn. 2012. Requirements for NAD PH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. J. Leukoc. Biol. 92:841-849. http://dx.doi.org/10.1189/jlb.1211601
55. Patel, K.D., G.A. Zimmerman, S.M. Prescott, R.P. McEver, and T.M. McIntyre. 1991. Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J. Cell Biol. 112:749-759. http://dx.doi.org/10.1083/jcb.112.4.749
56. Pillai, P.S., R.D. Molony, K. Martinod, H. Dong, I.K. Pang, M.C. Tal, A.G. Solis, P. Bielecki, S. Mohanty, M. Trentalange, et al. 2016. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science. 352:463-466. http://dx.doi.org/10.1126/science.aaf3926
57. Pugh, K.G., and J.Y. Wei. 2001. Clinical implications of physiological changes in the aging heart. Drugs Aging. 18:263-276. http://dx.doi.org/10.2165/00002512-200118040-00004
58. Quillard, T., H.A. Araujo, G. Franck, E. Shvartz, G. Sukhova, and P. Libby. 2015. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur. Heart J. 36:1394-1404. http://dx.doi.org/10.1093/eurheartj/ehv044
59. Radic, M., and T.N. Marion. 2013. Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity. Semin. Immunopathol. 35:465-480. http://dx.doi.org/10.1007/s00281-013-0376-6
60. Savchenko, A.S., J.I. Borissoff, K. Martinod, S.F. De Meyer, M. Gallant, L. Erpenbeck, A. Brill, Y. Wang, and D.D. Wagner. 2014a. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood. 123:141-148. http://dx.doi.org/10.1182/blood-2013-07-514992
61. Savchenko, A.S., K. Martinod, M.A. Seidman, S.L. Wong, J.I. Borissoff, G. Piazza, P. Libby, S.Z. Goldhaber, R.N. Mitchell, and D.D. Wagner. 2014b. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J. Thromb. Haemost. 12:860-870. http://dx.doi.org/10.1111/jth.12571
62. Schröder, A.K., and L. Rink. 2003. Neutrophil immunity of the elderly. Mech. Ageing Dev. 124:419-425. http://dx.doi.org/10.1016/S0047-6374(03)00017-4
63. Sirker, A., M. Zhang, C. Murdoch, and A.M. Shah. 2007. Involvement of NAD PH oxidases in cardiac remodelling and heart failure. Am. J. Nephrol. 27:649-660. http://dx.doi.org/10.1159/000109148
64. Siwik, D.A., P.J. Pagano, and W.S. Colucci. 2001. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am. J. Physiol. Cell Physiol. 280:C53-C60.
65. Sohal, R.S., and R. Weindruch. 1996. Oxidative stress, caloric restriction, and aging. Science. 273:59-63. http://dx.doi.org/10.1126/science.273.5271.59
66. Sun, M., M. Chen, F. Dawood, U. Zurawska, J.Y. Li, T. Parker, Z. Kassiri, L.A. Kirshenbaum, M. Arnold, R. Khokha, and P.P. Liu. 2007. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation. 115:1398-1407. http://dx.doi.org/10.1161/CIR CUL ATI ONA HA.106.643585
67. Sur Chowdhury, C., S. Giaglis, U.A. Walker, A. Buser, S. Hahn, and P. Hasler. 2014. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res. Ther. 16:R122. http://dx.doi.org/10.1186/ar4579
68. Tabas, I., and C.K. Glass. 2013. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 339:166-172. http://dx.doi.org/10.1126/science.1230720
69. Tarnavski, O., J.R. McMullen, M. Schinke, Q. Nie, S. Kong, and S. Izumo. 2004. Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiol. Genomics. 16:349-360.
70. Thévenaz, P., and M. Unser. 2007. User-friendly semiautomated assembly of accurate image mosaics in microscopy. Microsc. Res. Tech. 70:135-146. http://dx.doi.org/10.1002/jemt.20393
71. Thomas, G.M., C. Carbo, B.R. Curtis, K. Martinod, I.B. Mazo, D. Schatzberg, S.M. Cifuni, T.A. Fuchs, U.H. von Andrian, J.H. Hartwig, et al. 2012. Extracellular DNA traps are associated with the pathogenesis of TRA LI in humans and mice. Blood. 119:6335-6343. http://dx.doi.org/10.1182/blood-2012-01-405183
72. van Beers, J.J., A.J. Zendman, R. Raijmakers, J. Stammen-Vogelzangs, and G.J. Pruijn. 2013. Peptidylarginine deiminase expression and activity in PAD2 knock-out and PAD4-low mice. Biochimie. 95:299-308. http://dx.doi.org/10.1016/j.biochi.2012.09.029
73. van Durme, Y.M., K.M. Verhamme, T. Stijnen, F.J. van Rooij, G.R. Van Pottelberge, A. Hofman, G.F. Joos, B.H. Stricker, and G.G. Brusselle. 2009. Prevalence, incidence, and lifetime risk for the development of COPD in the elderly: the Rotterdam study. Chest. 135:368-377. http://dx.doi.org/10.1378/chest.08-0684
74. Varagic, J., D. Susic, and E. Frohlich. 2001. Heart, aging, and hypertension. Curr. Opin. Cardiol. 16:336-341. http://dx.doi.org/10.1097/00001573-200111000-00004
75. Wagner, D.D., and P.S. Frenette. 2008. The vessel wall and its interactions. Blood. 111:5271-5281. http://dx.doi.org/10.1182/blood-2008-01-078204
76. Wang, Y., J. Wysocka, J. Sayegh, Y.H. Lee, J.R. Perlin, L. Leonelli, L.S. Sonbuchner, C.H. McDonald, R.G. Cook, Y. Dou, et al. 2004. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 306:279-283. http://dx.doi.org/10.1126/science.1101400
77. Wang, Y., M. Li, S. Stadler, S. Correll, P. Li, D. Wang, R. Hayama, L. Leonelli, H. Han, S.A. Grigoryev, et al. 2009. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184:205-213. http://dx.doi.org/10.1083/jcb.200806072
78. Warnatsch, A., M. Ioannou, Q. Wang, and V. Papayannopoulos. 2015. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 349:316-320. http://dx.doi.org/10.1126/science.aaa8064
79. Wei, J.Y. 1992. Age and the cardiovascular system. N. Engl. J. Med. 327:1735-1739. http://dx.doi.org/10.1056/NEJM199212103272408
80. high macrophages accumulate first in the heart in a model of murine pressure-overload. PLoS One. 9:e112710. http://dx.doi.org/10.1371/journal.pone.0112710
81. Woessner, J.F. Jr. 1961. The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch. Biochem. Biophys. 93:440-447. http://dx.doi.org/10.1016/0003-9861(61)90291-0
82. Wong, S.L., M. Demers, K. Martinod, M. Gallant, Y. Wang, A.B. Goldfine, C.R. Kahn, and D.D. Wagner. 2015. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 21:815-819. http://dx.doi.org/10.1038/nm.3887
83. Wynn, T.A., and T.R. Ramalingam. 2012. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18:1028-1040. http://dx.doi.org/10.1038/nm.2807
84. Xu, J., X. Zhang, R. Pelayo, M. Monestier, C.T. Ammollo, F. Semeraro, F.B. Taylor, N.L. Esmon, F. Lupu, and C.T. Esmon. 2009. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15:1318-1321. http://dx.doi.org/10.1038/nm.2053
85. Yang, B., D.F. Larson, and R. Watson. 1999. Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships. Am. J. Physiol. 277:H1906-H1913.
86. Zenaro, E., E. Pietronigro, V. Della Bianca, G. Piacentino, L. Marongiu, S. Budui, E. Turano, B. Rossi, S. Angiari, S. Dusi, et al. 2015. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21:880-886. http://dx.doi.org/10.1038/nm.3913
87. Zhang, D., G. Chen, D. Manwani, A. Mortha, C. Xu, J.J. Faith, R.D. Burk, Y. Kunisaki, J.E. Jang, C. Scheiermann, et al. 2015. Neutrophil ageing is regulated by the microbiome. Nature. 525:528-532. http://dx.doi.org/10.1038/nature15367