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The therapeutic potential of BRD4 in cardiovascular disease

Hypertension Research volume 43, pages 1006–1014 (2020)Cite this article

Abstract

Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra terminal (BET) protein family that has gained wide attention in the field of cancer due to its role in the formation of super enhancers (SEs) and the regulation of oncogene expression. However, there is increasing evidence that BRD4 also plays a pivotal role in a variety of cardiovascular diseases, suggesting that understanding the mechanisms of BRD4 in these diseases is important to advance studies and clinical treatment. In this article, we summarize the mechanisms of BRD4 in cardiovascular diseases, including pulmonary arterial hypertension, heart failure, atherosclerosis, and hypertension. In addition, we discuss small molecule inhibitors of BRD4 as novel therapeutic strategies for cardiovascular diseases.

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References

  1. Reiner Ž. Statins in the primary prevention of cardiovascular disease. Nat Rev Cardiol. 2013;10:453–64.

    CAS  PubMed  Google Scholar 

  2. Katsuya T, Rakugi H, Ogihara T. Inflammation and salt sensitivity in the early state of hypertension. Hypertens Res. 2007;30:105–7.

    CAS  PubMed  Google Scholar 

  3. Yang C, Lu M, Chen W, He Z, Hou X, Feng M, et al. Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques. J Exp Med. 2019;216:1182–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zanconato F, Battilana G, Forcato M, Filippi L, Azzolin L, Manfrin A, et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat Med. 2018;24:1599–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Donati B, Lorenzini E, Ciarrocchi A. BRD4 and Cancer: going beyond transcriptional regulation. Mol Cancer 2018;17:164. (abstract 229)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Spiltoir JI, Stratton MS, Cavasin MA, Demos-Davies K, Reid BG, Qi J, et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol. 2013;63:175–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. 2007;282:13141–5.

    CAS  PubMed  Google Scholar 

  8. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513:124–8.

    CAS  PubMed  Google Scholar 

  9. Morinière J, Rousseaux S, Steuerwald U, Soler-López M, Curtet S, Vitte AL, et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 2009;461:664–8.

    PubMed  Google Scholar 

  10. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell 2014;54:728–36.

    CAS  PubMed  Google Scholar 

  11. Meloche J, Potus F, Vaillancourt M, Bourgeois A, Johnson I, Deschamps L, et al. Bromodomain-containing protein 4 the epigenetic origin of pulmonary arterial hypertension. Circ Res. 2015;117:525–35.

    CAS  PubMed  Google Scholar 

  12. Stratton MS, Lin CY, Anand P, Tatman PD, Ferguson BS, Wickers ST, et al. Signal-dependent recruitment of BRD4 to cardiomyocyte super-enhancers is suppressed by a microRNA. Cell Rep. 2016;16:1366–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tsujikawa LM, Fu L, Das S, Halliday C, Rakai BD, Stotz SC, et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenet. 2019;11:102. (abstract 357)

    Google Scholar 

  14. Klein K, Kabala PA, Grabiec AM, Gay RE, Kolling C, Lin LL, et al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 2016;75:422–9.

    CAS  PubMed  Google Scholar 

  15. Shioji K, Izuhara M, Mitsuoka H, Uegaito T, Matsuda M. Achievement rates of Japan Atherosclerosis Society Guidelines 2007 LDL-cholesterol goals with rosuvastatin or atorvastatin in patients who had not achieved their goal with atorvastatin. Cardiovasc Ther. 2014;32:97–104.

    CAS  PubMed  Google Scholar 

  16. Ishigaki Y, Kono S, Katagiri H, Oka Y, Oikawa S. Elevation of HDL-C in response to statin treatment is involved in the regression of carotid atherosclerosis. J Atheroscler Thromb. 2014;21:1055–65.

    PubMed  Google Scholar 

  17. Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010;55:2727–35.

    PubMed  Google Scholar 

  18. Nicholls SJ, Gordon A, Johansson J, Wolski K, Ballantyne CM, Kastelein JJ, et al. Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease. J Am Coll Cardiol. 2011;57:1111–9.

    CAS  PubMed  Google Scholar 

  19. McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Attwell S, Campeau E, et al. RVX-208, an Inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS ONE 2013;8:e83190. https://doi.org/10.1371/journal.pone.0083190.

    PubMed  PubMed Central  Google Scholar 

  20. Bäck M, Yurdagul A Jr, Tabas I, Öörni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16:389–406.

    PubMed  PubMed Central  Google Scholar 

  21. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019;124:315–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Escárcega RO, García-Carrasco M, Fuentes-Alexandro S, Jara LJ, Rojas-Rodriguez J, Escobar-Linares LE, et al. Insulin resistance, chronic inflammatory state and the link with systemic lupus erythematosus-related coronary disease. Autoimmun Rev. 2006;6:48–53.

    PubMed  Google Scholar 

  23. Huang B, Yang XD, Zhou MM, Ozato K, Chen LF. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol Cell Biol. 2009;29:1375–87.

    CAS  PubMed  Google Scholar 

  24. Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, et al. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 2014;56:219–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ramji DP, Davies TS. Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev. 2015;26:673–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38.

    CAS  PubMed  Google Scholar 

  27. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N. Engl J Med. 2005;352:1685–95.

    CAS  PubMed  Google Scholar 

  28. Zhou B, Mu J, Gong Y, Lu C, Zhao Y, He T, et al. Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression. Redox Biol. 2017;11:390–402.

    CAS  PubMed  Google Scholar 

  29. Gavrilin MA, Mitra S, Seshadri S, Nateri J, Berhe F, Hall MW, et al. Pyrin critical to macrophage IL-1beta response to Francisella challenge. J Immunol. 2009;182:7982–9.

    CAS  PubMed  Google Scholar 

  30. Tong G, Wu X, Cheng B, Li L, Li X, Li Z, et al. Knockdown of HOXA-AS2 suppresses proliferation and induces apoptosis in colorectal cancer. Am J Transl Res. 2017;9:4545–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lian Y, Li Z, Fan Y, Huang Q, Chen J, Liu W, et al. The lncRNA-HOXA-AS2/EZH2/LSD1 oncogene complex promotes cell proliferation in pancreatic cancer. Am J Transl Res. 2017;9:5496–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu X, Liu Y, Yu J, Du J, Guo R, Feng Y, et al. LncRNA HOXA-AS2 represses endothelium inflammation by regulating the activity of NF-κB signaling. Atherosclerosis 2019;281:38–46.

    CAS  PubMed  Google Scholar 

  33. Jain T, Nikolopoulou EA, Xu Q, Qu A. Hypoxia inducible factor as a therapeutic target for atherosclerosis. Pharm Ther. 2018;183:22–33.

    CAS  Google Scholar 

  34. Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res. 2018;114:590–600.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Baud'huin M, Lamoureux F, Jacques C, Rodriguez Calleja L, Quillard T, Charrier C, et al. Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis. Bone 2017;94:10–21.

    CAS  PubMed  Google Scholar 

  36. Gilham D, Tsujikawa LM, Sarsons CD, Halliday C, Wasiak S, Stotz SC, et al. Apabetalone downregulates factors and pathways associated with vascular calcification. Atherosclerosis 2019;280:75–84.

    CAS  PubMed  Google Scholar 

  37. Zhang L, Tang L, Wei J, Lao L, Gu W, Hu Q, et al. Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats: the role of epigenetic mechanisms. J Hypertens. 2014;32:2188–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tang LL, Zhang LY, Lao LJ, Hu QY, Gu WZ, Fu LC, et al. Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction. Respir Res. 2015;16:66.

    PubMed  PubMed Central  Google Scholar 

  39. Friedman D, Szmuszkovicz J, Rabai M, Detterich JA, Menteer J, Wood JC. Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity. J Heart Lung Transplant 2012;31:642–7.

    PubMed  PubMed Central  Google Scholar 

  40. Mumby S, Gambaryan N, Meng C, Perros F, Humbert M, Wort SJ, et al. Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension. Respirology 2017;22:157–64.

    PubMed  Google Scholar 

  41. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795–803.

    CAS  PubMed  Google Scholar 

  42. Huang M, Qiu Q, Xiao Y, Zeng S, Zhan M, Shi M, et al. BET bromodomain suppression inhibits VEGF-induced angiogenesis and vascular permeability by blocking VEGFR2-mediated activation of PAK1 and eNOS. Sci Rep. 2016;6:23770. (abstract 197)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen J, Fu Y, Day DS, Sun Y, Wang S, Liang X, et al. VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. Nat Commun. 2017;8:383. (abstract 179)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 2007;104:11418–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang B, Zhang M, Takayama T, Shi X, Roenneburg DA, Kent KC, et al. BET bromodomain blockade mitigates intimal hyperplasia in rat carotid arteries. EBioMedicine 2015;2:1650–61.

    PubMed  PubMed Central  Google Scholar 

  46. Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 2014;129:786–97.

    CAS  PubMed  Google Scholar 

  47. Floyd SR, Pacold ME, Huang Q, Clarke SM, Lam FC, Cannell IG, et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 2013;498:246–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer 2012;12:465–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Van der Feen DE, Kurakula K, Tremblay E, Boucherat O, Bossers GP, Szulcek R, et al. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2019;200:910–20.

    PubMed  Google Scholar 

  50. Bourgeois A, Lambert C, Habbout K, Ranchoux B, Paquet-Marceau S, Trinh I, et al. FOXM1 promotes pulmonary artery smooth muscle cell expansion in pulmonary arterial hypertension. J Mol Med (Berl). 2018;96:223–35.

    CAS  PubMed  Google Scholar 

  51. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 2004;169:764–9.

    PubMed  Google Scholar 

  52. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.

    CAS  PubMed  Google Scholar 

  53. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev. 2007;87:245–313.

    CAS  PubMed  Google Scholar 

  54. Wedgwood S, Steinhorn RH. Role of reactive oxygen species in neonatal pulmonary vascular disease. Antioxid Redox Signal 2014;21:1926–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu H, Wang L, Weng X, Chen H, Du Y, Diao C, et al. Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. Redox Biol. 2019;24:101195. (abstract 209)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ijaz T, Jamaluddin M, Zhao Y, Zhang Y, Jay J, Finnerty CC, et al. Coordinate activities of BRD4 and CDK9 in the transcriptional elongation complex are required for TGFβ-induced Nox4 expression and myofibroblast transdifferentiation. Cell Death Dis. 2017;8:e2606. https://doi.org/10.1038/cddis.2016.434.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Anand V, Roy SS, Archer SL, Weir EK, Garg SK, Duval S, et al. Trends and outcomes of pulmonary arterial hypertension-related hospitalizations in the United States: analysis of the Nationwide Inpatient Sample Database from 2001 through 2012. JAMA Cardiol. 2016;1:1021–9.

    PubMed  Google Scholar 

  58. Meloche J, Lampron MC, Nadeau V, Maltais M, Potus F, Lambert C, et al. Implication of inflammation and epigenetic readers in coronary artery remodeling in patients with pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2017;37:1513–23.

    CAS  PubMed  Google Scholar 

  59. Hill JA, Olson EN. Cardiac plasticity. N. Engl J Med. 2008;358:1370–80.

    CAS  PubMed  Google Scholar 

  60. Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 2013;154:569–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Korb E, Herre M, Zucker-Scharff I, Darnell RB, Allis CD. BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat Neurosci. 2015;18:1464–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51:600–6.

    CAS  PubMed  Google Scholar 

  63. Duan Q, McMahon S, Anand P, Shah H, Thomas S, Salunga HT, et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci Transl Med. 2017;9:eaah5084. https://doi.org/10.1126/scitranslmed.aah5084.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sun Y, Xie Y, Du L, Sun J, Liu Z. Inhibition of BRD4 attenuates cardiomyocyte apoptosis via NF-ÎşB pathway in a rat model of myocardial infarction. Cardiovasc Ther. 2018;36:e12320. https://doi.org/10.1111/1755-5922.

    Article  Google Scholar 

  65. Postlethwaite AE, Shigemitsu H, Kanangat S. Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol. 2004;16:733–8.

    PubMed  Google Scholar 

  66. Strieter RM, Keeley EC, Hughes MA, Burdick MD, Mehrad B. The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. J Leukoc Biol. 2009;86:1111–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE. Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal 2012;24:1031–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Song S, Liu L, Yu Y, Zhang R, Li Y, Cao W, et al. Inhibition of BRD4 attenuates transverse aortic constriction- and TGF-β-induced endothelial-mesenchymal transition and cardiac fibrosis. J Mol Cell Cardiol. 2019;127:83–96.

    CAS  PubMed  Google Scholar 

  69. Van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest. 2013;123:37–45.

    PubMed  PubMed Central  Google Scholar 

  70. Yang YM, Shi RH, Xu CX, Li L. BRD4 expression in patients with essential hypertension and its effect on blood pressure in spontaneously hypertensive rats. J Am Soc Hypertens. 2018;12:e107–17.

    CAS  PubMed  Google Scholar 

  71. Zhang P, Li R, Xiao H, Liu W, Zeng X, Xie G, et al. BRD4 inhibitor AZD5153 suppresses the proliferation of colorectal cancer cells and sensitizes the anticancer effect of PARP inhibitor. Int J Biol Sci. 2019;15:1942–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Liu S, Li F, Pan L, Yang Z, Shu Y, Lv W, et al. BRD4 inhibitor and histone deacetylase inhibitor synergistically inhibit the proliferation of gallbladder cancer in vitro and in vivo. Cancer Sci. 2019;110:2493–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature 2010;468:1067–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sun Y, Huang J, Song K. BET protein inhibition mitigates acute myocardial infarction damage in rats via the TLR4/TRAF6/NF-κB pathway. Exp Ther Med. 2015;10:2319–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Huang M, Zeng S, Zou Y, Shi M, Qiu Q, Xiao Y, et al. The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation. Br J Pharmacol. 2017;174:101–15.

    CAS  PubMed  Google Scholar 

  76. Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci USA 2013;110:19754–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Jahagirdar R, Zhang H, Azhar S, Tobin J, Attwell S, Yu R, et al. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis 2014;236:91–100.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases, the Key Laboratory of Reproductive Genetics (Zhejiang University), the Ministry of Education, and by grants from the National Natural Science Foundation of China (Nos. 81471480, 81630037, and 81501293).

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  1. Department of Neonatology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Shigang Lin & Lizhong Du

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Lin, S., Du, L. The therapeutic potential of BRD4 in cardiovascular disease. Hypertens Res 43, 1006–1014 (2020). https://doi.org/10.1038/s41440-020-0459-4

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