Targeting the adventitial microenvironment in pulmonary hypertension: A potential approach to therapy that considers epigenetic change

Pulmonary Circulation

Volumn 2, Issue 1, 2012, Pages 3-14

  Stenmark, Kurt R ^a   Frid, Maria G ^a   Yeager, Michael ^a   Li, Min ^a   Riddle, Suzette ^a   McKinsey, Timothy ^b   El Kasmi, Karim C ^a  

^a UNIVERSITY OF COLORADO   (United States)

^b UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

Author keywords

Adventitial; Epigenetics; Fibroblasts; Pulmonary hypertension

Indexed keywords

EID: 84873693794     PISSN: 20458932     EISSN: 20458940     Source Type: Journal    
DOI: 10.4103/2045-8932.94817     Document Type: Review

References (108)

1. Di Wang H, Ratsep MT, Chapman A, Boyd R. Adventitial fibroblasts in vascular structure and function: The role of oxidative stress and beyond. Can J Physiol Pharmacol 2010;88:177-86.
2. Haurani MJ, Pagano PJ. Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovascular Res 2007;75:679-89.
3. Majesky MW, Dong XR, Hoglund V, Mahoney WM Jr, Daum G. The adventitia: A dynamic interface containing resident progenitor cells. Arterioscler Thromb Vasc Biol 2011;31:1530-9.
4. Stenmark K, Nozik-Grayck E, Gerasimovskaya E, Anwar A, Li M, Riddle S, et al. The Adventitia: Essential Role in Pulmonary Vascular Remodeling. Compr Physiol 2011;1:141-61.
5. Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol 1997;151:317-22.
6. Kitamura H, Cambier S, Somanath S, Barker T, Minagawa S, Markovics J, et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin alphavbeta8-mediated activation of TGF-beta. J Clin Invest. 2011;121:2863-75.
7. Wei J, Bhattacharyya S, Tourtellotte WG, Varga J. Fibrosis in systemic sclerosis: Emerging concepts and implications for targeted therapy. Autoimmun Rev 2011;10:267-75.
8. Flavell SJ, Hou TZ, Lax S, Filer AD, Salmon M, Buckley CD. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol 2008;153 Suppl 1:S241-6.
9. Buckley CD. Why does chronic inflammation persist: An unexpected role for fibroblasts. Immunol Lett 2011;138:12-4.
10. Sakao S, Tatsumi K, Voelkel NF. Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2010;43:629-34.
11. Chizzolini C, Brembilla NC, Montanari E, Truchetet ME. Fibrosis and immune dysregulation in systemic sclerosis. Autoimmun Rev 2011;10: 276-81.
12. Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature Med 2009;15:774-80.
13. Neumann E, Lefevre S, Zimmermann B, Gay S, Muller-Ladner U. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010;16:458-68.
14. Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D, Salmon M. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol 2001;22:199-204.
15. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovascular Res 2007;75:640-8.
16. Capers QT, Alexander RW, Lou P, De Leon H, Wilcox JN, Ishizaka N, et al. Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats. Hypertension 1997;30:1397-402.
17. Csanyi G, Taylor WR, Pagano PJ. NOX and inflammation in the vascular adventitia. Free Radical Biol Med 2009;47:1254-66.
18. Jabs A, Okamoto E, Vinten-Johansen J, Bauriedel G, Wilcox JN. Sequential patterns of chemokine-and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries. Atherosclerosis 2007;192;75-84.
19. Okamoto E, Couse T, De Leon H, Vinten-Johansen J, Goodman RB, Scott NA, et al. Perivascular inflammation after balloon angioplasty of porcine coronary arteries. Circulation 2001;104:2228-35.
20. Tieu BC, Lee C, Sun H, Lejeune W, Recinos A 3rd, Ju X, et al. An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 2009;119: 3637-51.
21. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007;204:2449-60.
22. Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DR Jr, Simari RD, et al. Apoptosis. Basic concepts and implications in coronary artery disease. Arterioscler Thromb Vasc Biol 1999;19:14-22.
23. Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 1996;93:2178-87.
24. Tang PC, Qin L, Zielonka J, Zhou J, Matte-Martone C, Bergaya S, et al. MyD88-dependent, superoxide-initiated inflammation is necessary for flowmediated inward remodeling of conduit arteries. J Exp Med 2008;205:3159-71.
25. Zhou J, Tang PC, Qin L, Gayed PM, Li W, Skokos EA, et al. CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses. J Exp Med 2010;207:1951-66.
26. Hoglund VJ, Dong XR, Majesky MW. Neointima formation: A local affair. Arterioscler Thromb Vasc Biol 2010;30:1877-9.
27. Daniel JM, Bielenberg W, Stieger P, Weinert S, Tillmanns H, Sedding DG. Time-course analysis on the differentiation of bone marrow-derived progenitor cells into smooth muscle cells during neointima formation. Arterioscler Thromb Vasc Biol 2010;30:1890-6.
28. Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-63.
29. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006;168:659-69.
30. Sahara M, Sata M, Morita T, Nakamura K, Hirata Y, Nagai R. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation 2007;115:509-17.
31. Stenmark KR, Davie NJ, Reeves JT, Frid MG. Hypoxia, leukocytes, and the pulmonary circulation. J Appl Physiol 2005;98:715-21.
32. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 2007;28:23-42, vii.
33. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009;54:S10-9.
34. West J, Harral J, Lane K, Deng Y, Ickes B, Crona D, et al. Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 2008;295:L744-55.
35. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circulation Res 2009;104:236-244, 228p following 244.
36. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007;115:1260-8.
37. Dempsey EC, Wick MJ, Karoor V, Barr EJ, Tallman DW, Wehling CA, et al. Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia. Am J Pathol 2009;174:782-96.
38. Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, et al. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 2004;164:253-62.
39. Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, et al. Sustained hypoxia promotes the development of a pulmonary arteryspecific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol 2009;297:L238-50.
40. Davie NJ, Crossno JT Jr, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: Contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 2004;286:L668-78.
41. Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol 2011;187:2711-22.
42. Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, et al. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol 2000;165:3423-9.
43. Langheinrich AC, Kampschulte M, Buch T, Bohle RM. Vasa vasorum and atherosclerosis-Quid novi? Thromb Haemost 2007;97:873-9.
44. Ritman EL, Lerman A. The dynamic vasa vasorum. Cardiovascular Res 2007;75:649-58.
45. Havelka GE, Kibbe MR. The vascular adventitia: Its role in the arterial injury response. Vasc Endovascular Surg 2011;45:381-90.
46. Bayer IM, Caniggia I, Adamson SL, Langille BL. Experimental angiogenesis of arterial vasa vasorum. Cell Tissue Res 2002;307:303-13.
47. Gossl M, Rosol M, Malyar NM, Fitzpatrick LA, Beighley PE, Zamir M, et al. Functional anatomy and hemodynamic characteristics of vasa vasorum in the walls of porcine coronary arteries. Anat Rec A Discov Mol Cell Evol Biol 2003;272:526-37.
48. Moreno PR, Purushothaman KR, Zias E, Sanz J, Fuster V. Neovascularization in human atherosclerosis. Curr Mol Med 2006;6:457-77.
49. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 2003;100:4736-41.
50. Numano F. Vasa vasoritis, vasculitis and atherosclerosis. Int J Cardiol 2000;75 Suppl 1, S1-8; discussion S17-19.
51. Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ. Hypothesis: Vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984;310:175-7.
52. Hartlapp I, Abe R, Saeed RW, Peng T, Voelter W, Bucala R, et al. Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. Faseb J 2001;15:2215-24.
53. Hayden MR, Tyagi SC. Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: A malignant transformation. Cardiovasc Diabetol. 2004;3:1.
54. Herrmann J, Best PJ, Ritman EL, Holmes DR, Lerman LO, Lerman A. Chronic endothelin receptor antagonism prevents coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Am Coll Cardiol 2002;39:1555-61.
55. Davie NJ, Gerasimovskaya EV, Hofmeister SE, Richman AP, Jones PL, Reeves JT, et al. Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: A process mediated by hypoxia and endothelin-1. Am J Pathol 2006;168:1793-807.
56. Mitzner W, Wagner EM. Vascular remodeling in the circulations of the lung. J Appl Physiol 2004;97:1999-2004.
57. Kimura H, Okada O, Tanabe N, Tanaka Y, Terai M, Takiguchi Y, et al. Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2001;164:319-24.
58. Montani D, Perros F, Gambaryan N, Girerd B, Dorfmuller P, Price LC, et al. C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2011;184: 116-23.
59. Nathan S, Noble P, Tuder R. Idiopathic pulmonary fibrosis and pulmonary hypertension: Connecting the dots. Am J Respir Crit Care Med 2007;175:875-80.
60. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004;432:332-7.
61. Egeblad M, Littlepage LE, Werb Z. The fibroblastic coconspirator in cancer progression. Cold Spring Harb Symp Quant Biol 2005;70:383-8.
62. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nature Rev 2006;6:392-401.
63. Mueller MM, Fusenig NE. Friends or foes-bipolar effects of the tumour stroma in cancer. Nature Rev 2004;4:839-49.
64. Radisky E, Radisky D. Stromal induction of breast cancer: Inflammation and invasion. Rev Endocr Metab Disord 2007;8:279-87.
65. Voelkel NF, Cool C. Pathology of pulmonary hypertension. Cardiol Clin 2004;22:343-51.
66. Smith PJ, Teichert-Kuliszewska K, Monge JC, Stewart DJ. Regulation of endothelin-B receptor mRNA expression in human endothelial cells by cytokines and growth factors. J Cardiovasc Pharmacol 1998;31 Suppl 1:S158-60.
67. Wilasrusmee C, Ondocin P, Bruch D, Shah G, Kittur S, Wilasrusmee S, et al. Amelioration of cyclosporin A effect on microvasculature by endothelin inhibitor. Surgery 2003;134:384-9.
68. Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 1994;54:6083-6.
69. Popovici RM, Irwin JC, Giaccia AJ, Giudice LC. Hypoxia and cAMP stimulate vascular endothelial growth factor (VEGF) in human endometrial stromal cells: Potential relevance to menstruation and endometrial regeneration. J Clin Endocrinol Metab 1999;84:2245-8.
70. Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, et al. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab 2000;85:402-9.
71. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda)2006;21:134-45.
72. Martin TA, Harding K, Jiang WG. Matrix-bound fibroblasts regulate angiogenesis by modulation of VE-cadherin. Eur J Clin Invest 2001;31:931-8.
73. Nakatsu MN, Sainson RC, Aoto JN, Taylor KL, Aitkenhead M, Perezdel-Pulgar S, et al. Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: The role of fibroblasts and Angiopoietin-1. Microvasc Res 2003;66:102-12.
74. Velazquez OC, Snyder R, Liu ZJ, Fairman RM, Herlyn M. Fibroblastdependent differentiation of human microvascular endothelial cells into capillary-like 3-dimensional networks. Faseb J 2002;16:1316-8.
75. Kroon ME, Koolwijk P, vander Vecht B, van Hinsbergh VW. Hypoxia in combination with FGF-2 induces tube formation by human microvascular endothelial cells in a fibrin matrix: Involvement of at least two signal transduction pathways. J Cell Sci 2001;114:825-33.
76. Martin TA, Harding KG, Jiang WG. Regulation of angiogenesis and endothelial cell motility by matrix-bound fibroblasts. Angiogenesis 1999;3:69-76.
77. Tille JC, Pepper MS. Mesenchymal cells potentiate vascular endothelial growth factor-induced angiogenesis in vitro. Exp Cell Res 2002;280:179-91.
78. Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL. Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids. J Clin Invest 1989;83:1267-76.
79. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2009;60:3613-22.
80. Firestein GS, Alvaro-Gracia JM, Maki R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol 1990;144:3347-53.
81. Brouty-Boye D, Pottin-Clemenceau C, Doucet C, Jasmin C, Azzarone B. Chemokines and CD40 expression in human fibroblasts. Eur J Immunol 2000;30;914-9.
82. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2000;2:361-7.
83. Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nature Med 2010;16:544-50.
84. Moodley YP, Misso NL, Scaffidi AK, Fogel-Petrovic M, McAnulty RJ, Laurent GJ, et al. Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol 2003;29:490-8.
85. Jakubzick C, Choi ES, Carpenter KJ, Kunkel SL, Evanoff H, Martinez FJ, et al. Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia. Am J Pathol 2004;164:1989-2001.
86. Carulli MT, Ong VH, Ponticos M, Shiwen X, Abraham DJ, Black CM, et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: Evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum 2005;52:3772-82.
87. Murray LA, Argentieri RL, Farrell FX, Bracht M, Sheng H, Whitaker B, et al. Hyper-responsiveness of IPF/UIP fibroblasts: Interplay between TGFbeta1, IL-13 and CCL2. Int J Biochem Cell Biol 2008;40:2174-82.
88. Kim GH, Ryan JJ, Marsboom G, Archer SL. Epigenetic mechanisms of pulmonary hypertension. Pulm Circ 2011;1:347-56.
89. Karouzakis E, Gay RE, Gay S, Neidhart M. Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nat Rev Rheumatol 2009;5:266-72.
90. Adcock IM. HDAC inhibitors as anti-inflammatory agents. Br J Pharmacol 2007;150:829-31.
91. Bush EW, McKinsey TA. Protein acetylation in the cardiorenal axis: The promise of histone deacetylase inhibitors. Circulation Res 2010;106: 272-84.
92. Kawabata T, Nishida K, Takasugi K, Ogawa H, Sada K, Kadota Y, et al. Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis. Arthritis Res Ther 2010;12:R133.
93. Horiuchi M, Morinobu A, Chin T, Sakai Y, Kurosaka M, Kumagai S. Expression and function of histone deacetylases in rheumatoid arthritis synovial fibroblasts. J Rheumatol 2009;36:1580-9.
94. Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, et al. Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. Br J Pharmacol 2010;159:1408-17.
95. Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 2010;3:5.
96. Halili MA, Andrews MR, Sweet MJ, Fairlie DP. Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem 2009;9:309-19.
97. Findeisen HM, Gizard F, Zhao Y, Qing H, Heywood EB, Jones KL, et al. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition. Arterioscler Thromb Vasc Biol 2011;31:851-60.
98. Neidhart M, Rethage J, Kuchen S, Kunzler P, Crowl RM, Billingham ME, et al. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: Association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 2000;43:2634-47.
99. Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, et al. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 2006;54:779-87.
100. Esteller M. Epigenetics in cancer. N Engl J Med 2008;358:1148-59.
101. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 2009;175:3-16.
102. Kottmann RM, Hogan CM, Phipps RP, Sime PJ. Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology 2009;14: 917-33.
103. Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, et al. Thy-1 promoter hypermethylation: A novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol 2008; 39:610-8.
104. Sanders YY, Tollefsbol TO, Varisco BM, Hagood JS. Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. Am J Respir Cell Mol Biol 2011;45:16-23.
105. Cavasin M, Demos-Davies K, Horn T, Walker L, Lemon D, Birdsey N, et al. Selective Class I HDAC Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Anti-Proliferative Mehanism. Circulation Res 2012;110:739-48.
106. Cho YK, Eom GH, Kee HJ, Kim HS, Choi WY, Nam KI, et al. Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circ J 2010;74:760-70.
107. Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, et al. Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am J Respir Crit Care Med 2011;183:1402-10.
108. Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Chemical phylogenetics of histone deacetylases. Nat Chem Biol 2010;6:238-43.