The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

  • Lee, Eunjo (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Song, Min-ji (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Lee, Hae-Ahm (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Kang, Seol-Hee (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Kim, Mina (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Yang, Eun Kyoung (Department of Physiology, Kyungpook National University School of Medicine) ;
  • Lee, Do Young (Translational Research Center, CrystalGenomics, Inc.) ;
  • Ro, Seonggu (Translational Research Center, CrystalGenomics, Inc.) ;
  • Cho, Joong Myung (Translational Research Center, CrystalGenomics, Inc.) ;
  • Kim, Inkyeom (Department of Pharmacology, Kyungpook National University School of Medicine)
  • Received : 2016.03.18
  • Accepted : 2016.04.26
  • Published : 2016.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

Keywords

References

  1. Yip GW, Fung JW, Tan YT, Sanderson JE. Hypertension and heart failure: a dysfunction of systole, diastole or both? J Hum Hypertens. 2009;23:295-306. https://doi.org/10.1038/jhh.2008.141
  2. Writing Group Members, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010;121:e46-215. https://doi.org/10.1161/CIRCULATIONAHA.109.192667
  3. Bush EW, McKinsey TA. Protein acetylation in the cardiorenal axis: the promise of histone deacetylase inhibitors. Circ Res. 2010;106:272-284. https://doi.org/10.1161/CIRCRESAHA.109.209338
  4. Smith KT, Workman JL. Introducing the acetylome. Nat Biotechnol. 2009;27:917-919. https://doi.org/10.1038/nbt1009-917
  5. Norris KL, Lee JY, Yao TP. Acetylation goes global: the emergence of acetylation biology. Sci Signal. 2009;2:pe76.
  6. Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 2004;338:17-31. https://doi.org/10.1016/j.jmb.2004.02.006
  7. Smith KT, Workman JL. Histone deacetylase inhibitors: anticancer compounds. Int J Biochem Cell Biol. 2009;41:21-25. https://doi.org/10.1016/j.biocel.2008.09.008
  8. Kang SH, Seok YM, Song MJ, Lee HA, Kurz T, Kim I. Histone deacetylase inhibition attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor in spontaneously hypertensive rats. Mol Pharmacol. 2015;87:782-791. https://doi.org/10.1124/mol.114.096974
  9. Lee HA, Lee DY, Cho HM, Kim SY, Iwasaki Y, Kim IK. Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ Res. 2013;112:1004-1012. https://doi.org/10.1161/CIRCRESAHA.113.301071
  10. Kee HJ, Bae EH, Park S, Lee KE, Suh SH, Kim SW, Jeong MH. HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity. Kidney Blood Press Res. 2013;37:229-239. https://doi.org/10.1159/000350148
  11. Cardinale JP, Sriramula S, Pariaut R, Guggilam A, Mariappan N, Elks CM, Francis J. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension. 2010;56:437-444. https://doi.org/10.1161/HYPERTENSIONAHA.110.154567
  12. Jang EJ, Seok YM, Lee JI, Cho HM, Sohn UD, Kim IK. 3',4'-Dimethoxythioflavone induces endothelium-dependent vasorelaxation through activation of epidermal growth factor receptor. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:339-350. https://doi.org/10.1007/s00210-012-0818-z
  13. Lv L, Tang YP, Han X, Wang X, Dong Q. Therapeutic application of histone deacetylase inhibitors for stroke. Cent Nerv Syst Agents Med Chem. 2011;11:138-149. https://doi.org/10.2174/187152411796011330
  14. McKinsey TA. Targeting inflammation in heart failure with histone deacetylase inhibitors. Mol Med. 2011;17:434-441.
  15. Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, Fairlie DP, Brown L. Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. Br J Pharmacol. 2010;159:1408-1417. https://doi.org/10.1111/j.1476-5381.2010.00637.x
  16. Ooi JY, Tuano NK, Rafehi H, Gao XM, Ziemann M, Du XJ, El-Osta A. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10:418-430. https://doi.org/10.1080/15592294.2015.1024406
  17. Lemon DD, Horn TR, Cavasin MA, Jeong MY, Haubold KW, Long CS, Irwin DC, McCune SA, Chung E, Leinwand LA, McKinsey TA. Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension. J Mol Cell Cardiol. 2011;51:41-50. https://doi.org/10.1016/j.yjmcc.2011.04.005
  18. Eom GH, Cho YK, Ko JH, Shin S, Choe N, Kim Y, Joung H, Kim HS, Nam KI, Kee HJ, Kook H. Casein kinase-2${\alpha}$1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart. Circulation. 2011;123:2392-2403. https://doi.org/10.1161/CIRCULATIONAHA.110.003665
  19. Nural-Guvener HF, Zakharova L, Nimlos J, Popovic S, Mastroeni D, Gaballa MA. HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation. Fibrogenesis Tissue Repair. 2014;7:10. https://doi.org/10.1186/1755-1536-7-10
  20. Williams SM, Golden-Mason L, Ferguson BS, Schuetze KB, Cavasin MA, Demos-Davies K, Yeager ME, Stenmark KR, McKinsey TA. Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes. J Mol Cell Cardiol. 2014;67:112-125. https://doi.org/10.1016/j.yjmcc.2013.12.013
  21. Tao H, Yang JJ, Hu W, Shi KH, Li J. HDAC6 Promotes Cardiac Fibrosis Progression through Suppressing RASSF1A Expression. Cardiology. 2016;133:18-26. https://doi.org/10.1159/000438781
  22. Chun SM, Lee JY, Choi J, Lee JH, Hwang JJ, Kim CS, Suh YA, Jang SJ. Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells. PLoS One. 2015;10:e0119379. https://doi.org/10.1371/journal.pone.0119379
  23. Hwang JJ, Kim YS, Kim T, Kim MJ, Jeong IG, Lee JH, Choi J, Jang S, Ro S, Kim CS. A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL. Invest New Drugs. 2012;30:1434-1442. https://doi.org/10.1007/s10637-011-9718-1
  24. Takebe M, Oishi H, Taguchi K, Aoki Y, Takashina M, Tomita K, Yokoo H, Takano Y, Yamazaki M, Hattori Y. Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis. J Surg Res. 2014;187:559-570. https://doi.org/10.1016/j.jss.2013.10.050
  25. Oh ET, Park MT, Choi BH, Ro S, Choi EK, Jeong SY, Park HJ. Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells. Invest New Drugs. 2012;30:435-442. https://doi.org/10.1007/s10637-010-9568-2

Cited by

  1. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis vol.10, pp.None, 2016, https://doi.org/10.1177/2040622319862697
  2. Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCA-Salt Hypertensive Rats vol.20, pp.3, 2016, https://doi.org/10.3390/ijms20030508
  3. Novel molecular therapeutic targets in cardiac fibrosis: a brief overview vol.97, pp.4, 2019, https://doi.org/10.1139/cjpp-2018-0430
  4. CG200745, a Novel HDAC Inhibitor, Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome vol.21, pp.4, 2016, https://doi.org/10.3390/ijms21041473
  5. Histone deacetylase inhibitor CG200745 ameliorates high-fat diet-induced hypertension via inhibition of angiotensin II production vol.393, pp.3, 2016, https://doi.org/10.1007/s00210-019-01749-5
  6. Acute Exposure to Fructose Impairs Endothelium-Dependent Relaxation via Oxidative Stress in Isolated Rat Aortic Rings vol.57, pp.4, 2020, https://doi.org/10.1159/000506684
  7. Epigenetic control of natriuretic peptides: implications for health and disease vol.77, pp.24, 2016, https://doi.org/10.1007/s00018-020-03573-0
  8. Sulforaphane Ameliorates Diabetes-Induced Renal Fibrosis through Epigenetic Up-Regulation of BMP-7 vol.45, pp.6, 2016, https://doi.org/10.4093/dmj.2020.0168