BET protein inhibition mitigates acute myocardial infarction damage in rats via the TLR4/TRAF6/NF-κB pathway

Sun,Yangli; Huang,Jie; Song,Kunpeng

doi:10.3892/etm.2015.2789

BET protein inhibition mitigates acute myocardial infarction damage in rats via the TLR4/TRAF6/NF-κB pathway

Authors:
- Yangli Sun
- Jie Huang
- Kunpeng Song
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Affiliations: Department of Cardiovascular Internal Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450007, P.R. China
Published online on: October 8, 2015 https://doi.org/10.3892/etm.2015.2789
Pages: 2319-2324

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Abstract

Acute myocardial infarction (AMI) is among the most serious cardiovascular diseases and is a leading cause of mortality in developed countries. Previous studies have indicated the central role played by the bromodomain (BRD) proteins, which belong to the BRD and extra‑terminal (BET) family, in gene control during heart failure pathogenesis. In addition, BET inhibition has been shown to suppress cardiomyocyte hypertrophy. However, the role of BET proteins in myocardial infarction remains unclear. The present study aimed to investigate whether BETs inhibition mitigates AMI, and explore the molecular mechanism underlying this effect. A rat model of acute myocardial infarction was established, and rats were divided into the sham, AMI and AMI + JQ1 groups. JQ1, a well‑known selective BRD inhibitor, was used to suppress BET domain family activity. The mRNA and protein expression levels of BRD2, BRD3 and BRD4 were evaluated using quantitative polymerase chain reaction and western blot analysis, respectively. In addition, the expression levels of markers of cardiac damage were determined using commercial kits. The results indicated that BRD2 and BRD4 mRNA and protein expression levels were significantly increased in the AMI group compared with those in the sham group. In addition, BET inhibition decreased AMI damage in vivo by reversing cardiac function injury, decreasing serum lactate dehydrogenase and creatine kinase‑MB isozyme activity, in addition to decreasing the expression levels of high‑sensitivity C‑reactive protein and interleukin‑6. Furthermore, the results suggested that Toll‑like receptor 4 (TLR4) signaling was activated by the increased expression of TLR4, TNF receptor‑associated factor 6 (TRAF6) and nuclear factor (NF)-κB during AMI. However, JQ1 treatment suppressed TLR4 signaling activation. In conclusion, the present results demonstrated that the inhibition of BET family proteins suppresses AMI, and that this effect was partially mediated by the inhibition of TLR4/TRAF6/NF-κB signaling.

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1	Ozaki K, Sato H, Inoue K, Tsunoda T, Sakata Y, Mizuno H, Lin TH, Miyamoto Y, Aoki A, Onouchi Y, et al: SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat Genet. 41:329–333. 2009. View Article : Google Scholar : PubMed/NCBI
2	Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, et al: ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 33:2569–2619. 2012. View Article : Google Scholar : PubMed/NCBI
3	White HD and Chew DP: Acute myocardial infarction. Lancet. 372:570–584. 2008. View Article : Google Scholar : PubMed/NCBI
4	Florence B and Faller DV: You bet-cha: A novel family of transcriptional regulators. Front Biosci. 6:D1008–D1018. 2001. View Article : Google Scholar : PubMed/NCBI
5	Florence BL and Faller DV: Drosophila female sterile (1) homeotic is a multifunctional transcriptional regulator that is modulated by Ras signaling. Dev Dyn. 237:554–564. 2008. View Article : Google Scholar : PubMed/NCBI
6	Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, et al: Small-molecule inhibition of BRDT for male contraception. Cell. 150:673–684. 2012. View Article : Google Scholar : PubMed/NCBI
7	Banerjee C, Archin N, Michaels D, Belkina AC, Denis GV, Bradner J, Sebastiani P, Margolis DM and Montano M: BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 92:1147–1154. 2012. View Article : Google Scholar : PubMed/NCBI
8	Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, et al: Suppression of inflammation by a synthetic histone mimic. Nature. 468:1119–1123. 2010. View Article : Google Scholar : PubMed/NCBI
9	Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146:904–917. 2011. View Article : Google Scholar : PubMed/NCBI
10	Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, et al: Selective inhibition of BET bromodomains. Nature. 468:1067–1073. 2010. View Article : Google Scholar : PubMed/NCBI
11	Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, et al: BET bromodomains mediate transcriptional pause release in heart failure. Cell. 154:569–582. 2013. View Article : Google Scholar : PubMed/NCBI
12	Haldar SM and McKinsey TA: BET-ting on chromatin-based therapeutics for heart failure. J Mol Cell Cardiol. 74:98–102. 2014. View Article : Google Scholar : PubMed/NCBI
13	Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146:904–917. 2011. View Article : Google Scholar : PubMed/NCBI
14	Tang X, Peng R, Ren Y, Apparsundaram S, Deguzman J, Bauer CM, Hoffman AE, Hamilton S, Liang Z, Zeng H, et al: BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis. Mol Pharmacol. 83:283–293. 2013. View Article : Google Scholar : PubMed/NCBI
15	Spiltoir J, Stratton MS, Cavasin MA, Demos-Davies K, Reid BG, Qi J, Bradner JE and McKinsey TA: BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol. 63:175–179. 2013. View Article : Google Scholar : PubMed/NCBI
16	Eckle T, Grenz A, Köhler D, Redel A, Falk M, Rolauffs B, Osswald H, Kehl F and Eltzschig HK: Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice. Am J Physiol Heart Circ Physiol. 291:H2533–H2540. 2006. View Article : Google Scholar : PubMed/NCBI
17	Marushige K: Activation of chromatin by acetylation of histone side chains. Proc Natl Acad Sci USA. 73:3937–3941. 1976. View Article : Google Scholar : PubMed/NCBI
18	Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK and Zhou MM: Structure and ligand of a histone acetyltransferase bromodomain. Nature. 399:491–496. 1999. View Article : Google Scholar : PubMed/NCBI
19	Jacobson RH, Ladurner AG, King DS and Tjian R: Structure and function of a human TAFII250 double bromodomain module. Science. 288:1422–1425. 2000. View Article : Google Scholar : PubMed/NCBI
20	Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P and Travers AA: The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J. 19:6141–6149. 2000. View Article : Google Scholar : PubMed/NCBI
21	Chung CW, Coste H, White JH, Mirguet O, Wilde J, Gosmini RL, Delves C, Magny SM, Woodward R, Hughes SA, et al: Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 54:3827–3838. 2011. View Article : Google Scholar : PubMed/NCBI
22	Frangogiannis NG, Smith CW and Entman ML: The inflammatory response in myocardial infarction. Cardiovasc Res. 53:31–47. 2002. View Article : Google Scholar : PubMed/NCBI
23	Freitas F, Brucker N, Durgante J, Bubols G, Bulcão R, Moro A, Charão M, Baierle M, Nascimento S, Gauer B, et al: Urinary 1-hydroxypyrene is associated with oxidative stress and inflammatory biomarkers in acute myocardial infarction. Int J Environ Res Public Health. 11:9024–9037. 2014. View Article : Google Scholar : PubMed/NCBI
24	Kang YU, Kim MJ, Choi JS, Kim CS, Bae EH, Ma SK, Ahn YK, Jeong MH, Kim YJ, Cho MC, et al: Other Korea Acute Myocardial Infarction Registry Investigators: Concomitant impact of high-sensitivity C-reactive protein and renal dysfunction in patients with acute myocardial infarction. Yonsei Med J. 55:132–140. 2014. View Article : Google Scholar : PubMed/NCBI
25	Wang XH, Liu SQ, Wang YL and Jin Y: Correlation of serum high-sensitivity C-reactive protein and interleukin-6 in patients with acute coronary syndrome. Genet Mol Res. 13:4260–4266. 2014. View Article : Google Scholar : PubMed/NCBI
26	Takeda K, Kaisho T and Akira S: Toll-like receptors. Annu Rev Immunol. 21:335–376. 2003. View Article : Google Scholar : PubMed/NCBI
27	Beutler B: Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 430:257–263. 2004. View Article : Google Scholar : PubMed/NCBI
28	Akira S, Uematsu S and Takeuchi O: Pathogen recognition and innate immunity. Cell. 124:783–801. 2006. View Article : Google Scholar : PubMed/NCBI
29	Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science. 282:2085–2088. 1998. View Article : Google Scholar : PubMed/NCBI
30	Lee JY, Ye J, Gao Z, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M and Galanos C: Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem. 278:37041–37051. 2003. View Article : Google Scholar : PubMed/NCBI
31	Arslan F, de Kleijn DP and Pasterkamp G: Innate immune signaling in cardiac ischemia. Nat Rev Cardiol. 8:292–300. 2011. View Article : Google Scholar : PubMed/NCBI
32	Timmers L, Pasterkamp G, de Hoog VC, Arslan F, Appelman Y and de Kleijn DP: The innate immune response in reperfused myocardium. Cardiovasc Res. 94:276–283. 2012. View Article : Google Scholar : PubMed/NCBI
33	Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL, Yada M, Pohlman TH and Verrier ED: Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg. 128:170–179. 2004. View Article : Google Scholar : PubMed/NCBI
34	Timmers L, Sluijter JP, van Keulen JK, Hoefer IE, Nederhoff MG, Goumans MJ, Doevendans PA, van Echteld CJ, Joles JA, Quax PH, et al: Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res. 102:257–264. 2008. View Article : Google Scholar : PubMed/NCBI
35	Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ, Agnew ML, Hampton CR, Rothnie CL, Spring DJ, et al: Inhibition of toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation. 114(Suppl 1): S1270–S1274. 2006.
36	van der Pouw Kraan TC, Bernink FJ, Yildirim C, Koolwijk P, Baggen JM, Timmers L, Beek AM, Diamant M, Chen WJ, van Rossum AC, et al: Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction. J Mol Cell Cardiol. 67:94–102. 2014. View Article : Google Scholar : PubMed/NCBI
37	Akira S and Takeda K: Toll-like receptor signaling. Nat Rev Immunol. 4:499–511. 2004. View Article : Google Scholar : PubMed/NCBI
38	Timmers L, van Keulen JK, Hoefer IE, Meijs MF, van Middelaar B, den Ouden K, van Echteld CJ, Pasterkamp G and de Kleijn DP: Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ Res. 104:699–706. 2009. View Article : Google Scholar : PubMed/NCBI
39	Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich RL, Campos AD, Myszka DG, et al: E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 16:658–666. 2009. View Article : Google Scholar : PubMed/NCBI