1932

Abstract

Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.

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2020-01-24
2024-06-20
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Literature Cited

  1. 1. 
    WHO (World Health Organ.) 2017. Cardiovascular diseases (CVDs). WHO https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
    [Google Scholar]
  2. 2. 
    Bloom D, Cafiero E, Jané-Llopis E, Abrahams-Gessel S, Bloom L et al. 2011. The Global Economic Burden of Non-Communicable Diseases Geneva: World Econ. Forum
    [Google Scholar]
  3. 3. 
    Sniderman AD, Furberg CD. 2008. Age as a modifiable risk factor for cardiovascular disease. Lancet 371:1547–49
    [Google Scholar]
  4. 4. 
    Steenman M, Lande G. 2017. Cardiac aging and heart disease in humans. Biophys. Rev. 9:131–37
    [Google Scholar]
  5. 5. 
    Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K et al. 2012. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2224–60
    [Google Scholar]
  6. 6. 
    Khera AV, Kathiresan S. 2017. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat. Rev. Genet. 18:331–44
    [Google Scholar]
  7. 7. 
    Touzé E, Rothwell PM. 2007. Heritability of ischaemic stroke in women compared with men: a genetic epidemiological study. Lancet Neurol 6:125–33
    [Google Scholar]
  8. 8. 
    O'Donnell CJ, Nabel EG. 2011. Genomics of cardiovascular disease. N. Engl. J. Med. 365:2098–109
    [Google Scholar]
  9. 9. 
    Loewe L, Hill WG. 2010. The population genetics of mutations: good, bad and indifferent. Philos. Trans. R. Soc. B 365:1153–67
    [Google Scholar]
  10. 10. 
    Martincorena I, Campbell PJ. 2015. Somatic mutation in cancer and normal cells. Science 349:1483–89
    [Google Scholar]
  11. 11. 
    Forsberg LA, Gisselsson D, Dumanski JP 2017. Mosaicism in health and disease—clones picking up speed. Nat. Rev. Genet. 18:128–42
    [Google Scholar]
  12. 12. 
    Luzzatto L. 2011. Somatic mutations in cancer development. Environ. Health 10:Suppl. 1S12
    [Google Scholar]
  13. 13. 
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371:2488–98
    [Google Scholar]
  14. 14. 
    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG et al. 2017. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377:111–21
    [Google Scholar]
  15. 15. 
    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA et al. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371:2477–87
    [Google Scholar]
  16. 16. 
    Gollob MH, Jones DL, Krahn AD, Danis L, Gong X-Q et al. 2006. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N. Engl. J. Med. 354:2677–88
    [Google Scholar]
  17. 17. 
    Bonnefond A, Skrobek B, Lobbens S, Eury E, Thuillier D et al. 2013. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat. Genet. 45:1040–43
    [Google Scholar]
  18. 18. 
    Vijg J. 2014. Somatic mutations, genome mosaicism, cancer and aging. Curr. Opin. Genet. Dev. 26:141–49
    [Google Scholar]
  19. 19. 
    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE et al. 2012. The origin and evolution of mutations in acute myeloid leukemia. Cell 150:264–78
    [Google Scholar]
  20. 20. 
    Bowman RL, Busque L, Levine RL 2018. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22:157–70
    [Google Scholar]
  21. 21. 
    Busque L, Mio R, Mattioli J, Brais E, Blais N et al. 1996. Nonrandom X-inactivation patterns in normal females: Lyonization ratios vary with age. Blood 88:59–65
    [Google Scholar]
  22. 22. 
    Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S et al. 2012. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44:1179–81
    [Google Scholar]
  23. 23. 
    Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z et al. 2012. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44:651–58
    [Google Scholar]
  24. 24. 
    Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR et al. 2012. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44:642–50
    [Google Scholar]
  25. 25. 
    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ et al. 2014. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20:1472–78
    [Google Scholar]
  26. 26. 
    Vineis P, Schatzkin A, Potter JD 2010. Models of carcinogenesis: an overview. Carcinogenesis 31:1703–9
    [Google Scholar]
  27. 27. 
    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA et al. 2015. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16
    [Google Scholar]
  28. 28. 
    Silver AJ, Jaiswal S. 2019. Clonal hematopoiesis: pre-cancer PLUS. Adv. Cancer Res. 141:85–128
    [Google Scholar]
  29. 29. 
    Shlush LI. 2018. Age-related clonal hematopoiesis. Blood 131:496–504
    [Google Scholar]
  30. 30. 
    Loh PR, Genovese G, Handsaker RE, Finucane HK, Reshef YA et al. 2018. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559:350–55
    [Google Scholar]
  31. 31. 
    Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT et al. 2017. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–52
    [Google Scholar]
  32. 32. 
    McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H et al. 2015. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 10:1239–45
    [Google Scholar]
  33. 33. 
    Young AL, Challen GA, Birmann BM, Druley TE 2016. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7:12484
    [Google Scholar]
  34. 34. 
    Henry CJ, Marusyk A, DeGregori J 2011. Aging-associated changes in hematopoiesis and leukemogenesis: What's the connection?. Aging 3:643–56
    [Google Scholar]
  35. 35. 
    Konieczny J, Arranz L. 2018. Updates on old and weary haematopoiesis. Int. J. Mol. Sci. 19:2567
    [Google Scholar]
  36. 36. 
    Desai P, Mencia-Trinchant N, Savenkov O, Simon MS, Cheang G et al. 2018. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24:1015–23
    [Google Scholar]
  37. 37. 
    Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N et al. 2018. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559:400–4
    [Google Scholar]
  38. 38. 
    Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Ecke A et al. 2019. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol 4:25–33
    [Google Scholar]
  39. 39. 
    Mas-Peiro S, Hoffmann J, Fichtlscherer S, Dorsheimer L, Rieger MA et al. 2019. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur Heart J 2019.ehz591
    [Google Scholar]
  40. 40. 
    Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J et al. 2017. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35:1598–605
    [Google Scholar]
  41. 41. 
    Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K et al. 2017. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol 18:100–11
    [Google Scholar]
  42. 42. 
    Sano S, Wang Y, Walsh K 2018. Clonal hematopoiesis and its impact on cardiovascular disease. Circ. J. 83:2–11
    [Google Scholar]
  43. 43. 
    Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A et al. 2017. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21:374–82
    [Google Scholar]
  44. 44. 
    Kahn JD, Miller PG, Silver AJ, Sellar RS, Bhatt S et al. 2018. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095–105
    [Google Scholar]
  45. 45. 
    Swisher EM, Harrell MI, Norquist BM, Walsh T, Brady M et al. 2016. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol 2:370–72
    [Google Scholar]
  46. 46. 
    Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwinski R, Rusin M 2015. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br. J. Cancer 112:1114–20
    [Google Scholar]
  47. 47. 
    Artomov M, Rivas MA, Genovese G, Daly MJ 2017. Mosaic mutations in blood DNA sequence are associated with solid tumor cancers. NPJ Genom. Med. 2:22
    [Google Scholar]
  48. 48. 
    Abegunde SO, Buckstein R, Wells RA, Rauh MJ 2018. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59:60–65
    [Google Scholar]
  49. 49. 
    Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM et al. 2018. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580–84
    [Google Scholar]
  50. 50. 
    Hasselbalch HC. 2012. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: Is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?. Blood 119:3219–25
    [Google Scholar]
  51. 51. 
    Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC et al. 2017. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–47
    [Google Scholar]
  52. 52. 
    Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K 2018. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123:335–41
    [Google Scholar]
  53. 53. 
    Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y et al. 2018. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71:875–86
    [Google Scholar]
  54. 54. 
    Sano S, Wang Y, Yura Y, Sano M, Oshima K et al. 2019. JAK2V617F-mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure. JACC Basic Transl. Sci 4:684–97
    [Google Scholar]
  55. 55. 
    Ito S, Shen L, Dai Q, Wu SC, Collins LB et al. 2011. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–3
    [Google Scholar]
  56. 56. 
    Fuster JJ, Walsh K. 2018. Somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease. Circ. Res. 122:523–32
    [Google Scholar]
  57. 57. 
    Zhang Q, Zhao K, Shen Q, Han Y, Gu Y et al. 2015. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525:389–93
    [Google Scholar]
  58. 58. 
    Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V et al. 2017. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–62
    [Google Scholar]
  59. 59. 
    Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M et al. 2009. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113:6403–10
    [Google Scholar]
  60. 60. 
    Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL et al. 2009. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 23:905–11
    [Google Scholar]
  61. 61. 
    Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG et al. 2009. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41:838–42
    [Google Scholar]
  62. 62. 
    Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D et al. 2011. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24
    [Google Scholar]
  63. 63. 
    Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I et al. 2011. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20:25–38
    [Google Scholar]
  64. 64. 
    Li Z, Cai X, Cai CL, Wang J, Zhang W et al. 2011. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118:4509–18
    [Google Scholar]
  65. 65. 
    He Y, Hara H, Nunez G 2016. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41:1012–21
    [Google Scholar]
  66. 66. 
    Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH et al. 2017. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377:1119–31
    [Google Scholar]
  67. 67. 
    Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T et al. 2018. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391:319–28
    [Google Scholar]
  68. 68. 
    Svennson E, Madar A, Campbell C, He Y, Sultan M et al. 2018. TET2-driven clonal hematopoiesis predicts response to canakinumab in the CANTOS trials: an exploratory analysis. Circulation 138:Suppl. 115111
    [Google Scholar]
  69. 69. 
    Lyko F. 2018. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 19:81–92
    [Google Scholar]
  70. 70. 
    Challen GA, Sun D, Jeong M, Luo M, Jelinek J et al. 2011. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44:23–31
    [Google Scholar]
  71. 71. 
    Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H 2007. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J. Exp. Med. 204:715–22
    [Google Scholar]
  72. 72. 
    Guryanova OA, Lieu YK, Garrett-Bakelman FE, Spitzer B, Glass JL et al. 2016. Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 30:1133–42
    [Google Scholar]
  73. 73. 
    Zhang X, Su J, Jeong M, Ko M, Huang Y et al. 2016. DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat. Genet. 48:1014–23
    [Google Scholar]
  74. 74. 
    Cole CB, Russler-Germain DA, Ketkar S, Verdoni AM, Smith AM et al. 2017. Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J. Clin. Investig. 127:3657–74
    [Google Scholar]
  75. 75. 
    Leoni C, Montagner S, Rinaldi A, Bertoni F, Polletti S et al. 2017. Dnmt3a restrains mast cell inflammatory responses. PNAS 114:E1490–99
    [Google Scholar]
  76. 76. 
    Gamper CJ, Agoston AT, Nelson WG, Powell JD 2009. Identification of DNA methyltransferase 3a as a T cell receptor–induced regulator of Th1 and Th2 differentiation. J. Immunol. 183:2267–76
    [Google Scholar]
  77. 77. 
    Pham D, Yu Q, Walline CC, Muthukrishnan R, Blum JS, Kaplan MH 2013. Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. J. Immunol. 191:902–11
    [Google Scholar]
  78. 78. 
    Yu Q, Zhou B, Zhang Y, Nguyen ET, Du J et al. 2012. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. PNAS 109:541–46
    [Google Scholar]
  79. 79. 
    Li X, Zhang Q, Ding Y, Liu Y, Zhao D et al. 2016. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17:806–15
    [Google Scholar]
  80. 80. 
    Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB et al. 2016. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 128:1121–28
    [Google Scholar]
  81. 81. 
    Hammarén HM, Virtanen AT, Raivola J, Silvennoinen O 2019. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine 118:48–63
    [Google Scholar]
  82. 82. 
    Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N et al. 2005. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–61
    [Google Scholar]
  83. 83. 
    Shammo JM, Stein BL. 2016. Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions. Hematology 2016:552–60
    [Google Scholar]
  84. 84. 
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G et al. 2005. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–97
    [Google Scholar]
  85. 85. 
    Mead AJ, Mullally A. 2017. Myeloproliferative neoplasm stem cells. Blood 129:1607–16
    [Google Scholar]
  86. 86. 
    James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F et al. 2005. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–48
    [Google Scholar]
  87. 87. 
    Lasho TL, Mesa R, Gilliland DG, Tefferi A 2005. Mutation studies in CD3+, CD19+ and CD34+ cell fractions in myeloproliferative disorders with homozygous JAK2V617F in granulocytes. Br. J. Haematol. 130:797–99
    [Google Scholar]
  88. 88. 
    Larsen TS, Christensen JH, Hasselbalch HC, Pallisgaard N 2007. The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. Br. J. Haematol. 136:745–51
    [Google Scholar]
  89. 89. 
    Ishii T, Bruno E, Hoffman R, Xu M 2006. Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood 108:3128–34
    [Google Scholar]
  90. 90. 
    Chiang Y-H, Chang Y-C, Lin H-C, Huang L, Cheng C-C et al. 2017. Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population. Oncotarget 8:76204–13
    [Google Scholar]
  91. 91. 
    Cordua S, Kjaer L, Skov V, Pallisgaard N, Hasselbalch HC, Ellervik C 2019. Prevalence and phenotypes of JAK2 V617F and calreticulin mutations in a Danish general population. Blood 134:469–79
    [Google Scholar]
  92. 92. 
    Wang W, Liu W, Fidler T, Wang Y, Tang Y et al. 2018. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2V617F mice. Circ. Res. 123:e35–47
    [Google Scholar]
  93. 93. 
    Wolach O, Sellar RS, Martinod K, Cherpokova D, McConkey M et al. 2018. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl. Med. 10:eaan8292
    [Google Scholar]
  94. 94. 
    Zhou Z, Zhang S, Ding S, Abudupataer M, Zhang Z et al. 2019. Excessive neutrophil extracellular trap formation aggravates acute myocardial infarction injury in apolipoprotein E deficiency mice via the ROS-dependent pathway. Oxidative Med. Cell. Longev. 2019:1209307–07
    [Google Scholar]
  95. 95. 
    Savchenko AS, Borissoff JI, Martinod K, De Meyer SF, Gallant M et al. 2014. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123:141–48
    [Google Scholar]
  96. 96. 
    Martinod K, Witsch T, Erpenbeck L, Savchenko A, Hayashi H et al. 2017. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214:439–58
    [Google Scholar]
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