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Bromodomain and Extra-Terminal Protein Inhibition in Atherosclerosis: Advantages and Disappointments

Alexander E. Berezin1, Alexander A. Berezin2

1 Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye, 69035, Ukraine;
2 Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, 69096, Ukraine.

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Alexander E. Berezin, Professor, MD, PhD, Senior Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University for Zaporozhye, 26, Mayakovsky Av., Zaporozhye, Postcode 69035, Ukraine.
Email: aeberezin@gmail.com; dr_berezin@mail.ru
Telephone: +: 380612894585
Fax: +38 0612894585
ORCID: orcid.org/0000-0002-0446-3999

Received: October 8, 2019
Revised: November 25, 2019
Accepted: December 1 2019
Published online: February 6, 2020

ABSTRACT

Major cardiovascular events (MACEs) are leading cause of premature death in general population, as well as in the patients with known atherosclerosis and coronary artery disease (CAD). Manifestation and progression of atherosclerosis is tightly related to systemic and local microvascular inflammation that accelerate vascular remodeling, triggers endothelial dysfunction and promote negative impact of the dyslipidemia on the vasculature. The bromodomain and extra terminal (BET) proteins were first proposed as anticancer drugs and then cardio and vascular protective effects were found. The aim of the mini review is summarize knowledge for BET protein inhibitors in prevention of poor clinical outcomes in patients with atherosclerosis and CAD. The results of pool analysis of some clinical trials, such as ASSERT, ASSURE-I, SUSTAIN, are disputed. It has been shown positive effects of apabetalone on the levels of Apo A-I and high-density lipoprotein cholesterol that was associated with significant declining of the systemic and local inflammatory reaction. There is evidence regarding that the apabetalone induced reverse of the atherosclerotic plaque volume.

Key words: Atherosclerosis; Coronary artery disease; Dyslipidemia; inflammation; bromodomain and extra terminal proteins

© 2020 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Berezin AE, Berezin AA. Bromodomain and Extra-Terminal Protein Inhibition in Atherosclerosis: Advantages and Disappointments. Journal of Cardiology and Therapy 2020; 7(1): 903-906 Available from: URL: http: //www.ghrnet.org/index.php/jct/article/view/2798

INTRODUCTION

Atherosclerosis is a leading cause of vascular remodeling that relates to cardiovascular (CV) complications, such as acute coronary syndrome (ACS), myocardial infarction (MI), stroke, and other major cardiovascular events (MACEs), which are associated with a high rate of morbidity and mortality[1]. It has been established that atherosclerosis is maladaptive process encompassing systemic, microvascular and in-plaque inflammation, altered immune response, dyslipidemia and lipid infiltration of sub-intima, endothelial dysfunction and impaired vascular reparation[2,3]. Activated macrophages play a pivotal role in atherosclerosis progression through initiating local inflammatory reaction, maintaining foam cells formation, triggering plaque cap instability and rupture, as well as supporting subsequent endothelial dysfunction and coagulative potency[4,5]. The numerous molecular mechanisms including TRIM59, SMAD, Janus Kinase (JNK) / Signal Transducer and Activator of Transcription (STAT) signaling pathway and PI3K/Akt, mitogen activated protein kinase and AMPK transduction mechanisms, which ensure a transformation of normal tissue-resident mononuclear-derived macrophages into atherosclerotic macrophages with various phenotypes (M1 and M2), are under close epigenetic control[6-8]. The histones’ acetylation is one of core element in the epigenetic regulation of post-processing transcription, which is realized by gene expression of the bromodomain and extra terminal (BET) proteins[9]. At physiological condition BET proteins occupy promoter sites on chromatin supporting an expression of housekeeping genes that ensure cell growth, differentiation, and metabolism[10]. At pathophysiological conditions pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, Il-8, and tumor necrosis factor-alpha, mediate translocation of transcription factor nuclear factor kappa-B (NF-κB) from cytoplasm to the nucleus with further binding to cis-regulatory regions of DNA[11]. The next step of DNA activation is p65 subunit-depended acetylation of NF-κB RelA complex resulting in a recruitment of the BRD4 from housekeeping genes, chromatin remodeling, and modification of transcription activity through cell cycle regulation of positive transcription elongation factor (P-TEFb) component stimulates RNA polymerase II-dependent transcription[12,13]. Overall, in vitro studies have been revealed that the BET proteins (predominantly BRD4) were powerful epigenetic co-activators of inflammatory response and atherogenesis via involvement in the JNK / STAT5 transcriptional activity[14,15].

First BET protein inhibitors were developed as anticancer drugs that have exhibited an ability not only to suppress expression of many oncogenic proteins (c-MYC and cyclin D1) by interplay with histone deacetylases, but upregulate pro-apoptotic proteins and down-regulate anti-apoptotic proteins (i.e., surviving)[16,17]. New era in clinical implementation of the BET protein inhibitors have become after description of the role of key elongation factors, such as P-TEFb, in pathogenesis of microvascular inflammation and atherosclerosis[18]. Moreover, the results of CANTOS trial have ascertained that directly targeting inflammation could be therapeutic strategy in CV diseases, because this approach was associated witch MACEs reduction[19]. The aim of the mini review is summarize knowledge for BET protein inhibitors in prevention of poor clinical outcomes in patients with atherosclerosis and coronary artery disease (CAD).

An impact of BET inhibitors on surrogate end points in CAD

Apabetalone (RVX-208) is a selective BET inhibitor which modulates lipid and inflammatory pathways implicated in CAD[20]. There is wide range of evidence regarding that the apabetalone having an ability to regulate inflammation-driven gene expression has ensured down-regulated expression of adhesion molecules (ICAM-1, VCAM-1, PECAM, and E-selectin), lowered endothelial cell-to- cell activation, suppressed macrophage inflammatory responses, declined circulating levels of thrombin, C-reactive protein, TNF-alphaα, IL-1beta, activated complement fragments C5a, C3b, and C5b-C6, and decreased sub-intimal oxidized lipids accumulation in atherosclerosis[21-23].

Administration of apabetalone in the ASSERT (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease) study for 12 weeks led to increase in the levels of apo A-I, HDL cholesterol, and large HDL particles[24]. Thus, apabetalone appeared to be an effective oral inducer of apolipoprotein A-I synthesis, the potent capability of which in CAD statin-treated patients had been established in three respectively small clinical trials (Table 1). The results of the ASSURE (ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation) trial have revealed that BET inhibitor apabetalone has demonstrated a significant reduction in coronary atherosclerotic plaque length and that the changes in plaque structure were strongly associated with on-treatment concentration of high-density lipoprotein (HDL) particles, but not HDL cholesterol or apolipoprotein A-1[25]. Apabetalone has exhibited an ability to stimulate an expression of apolipoprotein AI gene that was associated with atherosclerotic plaque volume regression through improvements in the plasma HDL profile in the SUSTAIN (Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation) study[26,27].

In general, apabetalone was well tolerated, and the treatment with apabetalone did not impact on the total rate of infections or infestations in patients, as well as transient and reversible elevations in liver transaminases 3 times and more the upper limit of normal ranges were found rarely and did not relate to bilirubin elevation[28].

Table 1 Clinical studies dedicated an efficacy, safety and tolerability of apabetalone.
Trial acronymFull nameStudy populationTreatmentConcomitant medicationThe primary efficacy parameter
ASSERTClinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease299 patients with CADRVX-208 100-300 mg bid or placebo for 12 weeksStatinspercent change in ApoA1 from baseline to 12 weeks post-randomization, and comparison of Compare the dose and time response relationships for major lipids (ApoA1, total cholesterol, HDL-C, LDL-C, non-HDL-C, TG, ApoB, LDL, and HDL-subclasses) over 4, 8 and 12 weeks�� time course
ASSURE-IThe ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation310 patients with angiographic coronary artery disease and low HDL-C levelsRVX-208 100 mg bid or placebo for 26 weeksStatinsthe nominal change in percent atheroma volume
SUSTAINStudy of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation172 with low HDL levelsRVX-208 100 mg bid or placebo for 24 weeksStatinspercentage change in HDL-C levels
BETonMACEEffect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk T2DM Subjects With CAD2425 patients with CAD and diabetes mellitusRVX-208 100 mg bid or placebo for 120 weeksIntensive statin therapyMACEs
Abbreviations: ApoA1, apo-lipoprotein A1, HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; ApoB, apo-lipoprotein B; CAD, coronary artery disease.

BET inhibitors for long-term prognosis of CV diseases and events

Recently performed pool analysis of three previously performed clinical trials dedicated of apabetalone administration in comparison with placebo has yielded significant decrease in MASEs (5.9% versus 10.4%; p = 0.02)[29]. Moreover, this effect was found to be prominent in in patients with diabetes mellitus (5.4% verssus 12.7%; p = 0.02), with baseline HDL cholesterol less than 39 mg/dl (5.5% versus 12.8%; p = 0.01), and with elevated high-sensitivity CRP levels (5.4% versus 14.2%; p = 0.02)[29]. Ongoing phase III BETonMACE (Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk T2DM Subjects With CAD, NCT02586155) clinical trial (n = 2425) that is currently being investigated to elucidate whether apabetalone may have serious clinical implications in diabetic patients with CAD. High intensity statin therapy is determined as co-medication for this study. MACEs are primary clinical outcomes and several biomarkers, such as CRP, alkaline phosphatase, fasting glucose, are considered as secondary outcomes to assay safety and tolerability. As it is expected the trial may help receiving strong evidence regarding of viability of new conception of the treatment of CAD and atherosclerosis. However, the patients who are being enrolled in the BETonMACE have to have established CAD according to prior myocardial infarction, percutaneous coronary intervention or visualization procedure confirmation. Therefore, diagnosis of diabetes mellitus should be verified according to new criteria of ADA. Finally, it is not clear whether patients with diabetes mellitus and CAD having contra-indications to intensive statin therapy will not be able to enroll in the study due to sophisticated study design and protocol and that it will not be influence on the frequency of MACEs in the active treatment group.

Conclusions

Early clinical studies have shown positive effects of apabetalone on the levels of Apo A-I and HDL cholesterol that was associated with significant declining of the systemic and local inflammatory reaction. There is evidence regarding that the apabetalone induced reverse of the atherosclerotic plaque volume. Whether this approach based on anti-inflammatory properties of apabetalone will be represented as potential brand new strategy to reduce CV risk is not clear and this assumption is addressed to the on-going BETonMACE study.

REFERENCES

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392 (10159): 1789-1858. [DOI: 10.1016/S0140-6736(18)32279-7]; [PMID: 30496104]

2. Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular Macrophages in Atherosclerosis. J Immunol Res. 2019; 2019: 4354786. [DOI: 10.1155/2019/4354786]; [PMID: 31886303]

3. Berezin AE. Endogenous vascular repair system in cardiovascular disease: The role of endothelial progenitor cells. Australasian Medical Journal. 2019; 12(2): 12(2): 42-48. [DOI: 10.21767/AMJ.2018.3464]

4. Koelwyn GJ, Corr EM, Erbay E, Moore KJ. Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol. 2018; 19(6): 526-537. [DOI: 10.1038/s41590-018-0113-3]; [PMID: 2977721]

5. Tabas I, Bornfeldt KE. Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res. 2016; 118(4): 653-67. [DOI: 10.1161/CIRCRESAHA.115.306256]; [PMID: 26892964]

6. Wang W, Zhang K, Zhang H, Li M, Zhao Y, Wang B, Xin W, Yang W, Zhang J, Yue S, Yang X. Underlying Genes Involved in Atherosclerotic Macrophages: Insights from Microarray Data Mining. Med Sci Monit. 2019; 25: 9949-9962. [DOI: 10.12659/MSM.917068]; [PMID: 31875420]

7. An Y, Ni Y, Xu Z, Shi S, He J, Liu Y, Deng KY, Fu M, Jiang M, Xin HB. TRIM59 expression is regulated by Sp1 and Nrf1 in LPS-activated macrophages through JNK signaling pathway. Cell Signal. 2019: 109522. [DOI: 10.1016/j.cellsig.2019.109522]; [PMID: 31883458]

8. Jiang T, Jiang D, You D, Zhang L, Liu L, Zhao Q. Agonism of GPR120 prevents ox-LDL-induced attachment of monocytes to endothelial cells. Chem Biol Interact. 2019: 108916. [DOI: 10.1016/j.cbi.2019.108916]; [PMID: 31870843]

9. Prinjha RK, Witherington J, Lee K. Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol Sci. 2012; 33: 146-153. [DOI: 10.1016/j.tips.2011.12.002]; [PMID: 22277300]

10. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005; 19: 523-534. [DOI: 10.1016/j.molcel.2005.06.027]; [PMID: 16109376]

11. LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008; 30: 51-60. [DOI: 10.1016/j.molcel.2008.01.018]; [PMID: 18406326]

12. 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: 1375-1387. [DOI: 10.1128/MCB.01365-08]; [PMID: 19103749]

13. Mota de Sá P, Richard AJ1, Stephens J. BET inhibition by JQ1 produces divergent transcriptional regulation of SOCS genes in adipocytes. Endocrinology. 2019. pii: bqz034. [DOI: 10.1210/endocr/bqz034]; [PMID: 31875887]; [Epub ahead of print]

14. Tsujikawa LM, Fu L, Das S, Halliday C, Rakai BD, Stotz SC, Sarsons CD, Gilham D, Daze E, Wasiak S, Studer D, Rinker KD, Sweeney M, Johansson JO, Wong NCW, Kulikowski E. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenetics. 2019; 11(1): 102. [DOI: 10.1186/s13148-019-0696-z]; [PMID: 31300040]

15. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005; 19: 523-534. [DOI: 10.1016/j.molcel.2005.06.027]; [PMID: 16109376]

16. Manzotti G, Ciarrocchi A, Sancisi V. Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers (Basel). 2019; 11(3). pii: E304. [DOI: 10.3390/cancers11030304]; [PMID: 30841549]; [Epub ahead of print]

17. Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017; 28: 1776-1787. [DOI: 10.1093/annonc/mdx157]; [PMID: 28838216]

18. Ramji DP, Davies TS. Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev. 2015; 26: 673-685. [DOI: 10.1016/j.cytogfr.2015.04.003]; [PMID: 2600519]

19. Aday AW, Ridker PM. Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond. Front Cardiovasc Med. 2018; 5: 62. [DOI: 10.3389/fcvm.2018.00062]; [PMID: 29922680]

20. Ghosh GC, Bhadra R, Ghosh RK, Banerjee K, Gupta A. RVX 208: A novel BET protein inhibitor, role as an inducer of apo A-I/HDL and beyond. Cardiovasc Ther. 2017; 35(4). [DOI: 10.1111/1755-5922.12265]; [PMID: 28423226]

21. Tsujikawa LM, Fu L, Das S, Halliday C, Rakai BD, Stotz SC, Sarsons CD, Gilham D, Daze E, Wasiak S, Studer D, Rinker KD, Sweeney M, Johansson JO, Wong NCW, Kulikowski E. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenetics. 2019; 11(1): 102. [DOI: 10.1186/s13148-019-0696-z]; [PMID: 29854980]

22. Dey A, Yang W, Gegonne A, Nishiyama A, Pan R, Yagi R, Grinberg A, Finkelman FD, Pfeifer K, Zhu J, Singer D, Zhu J, Ozato K. BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J. 2019; 38(7). pii: e100293. [DOI: 10.15252/embj.2018100293]; [PMID: 3084209]

23. Wasiak S, Gilham D, Tsujikawa LM, Halliday C, Calosing C, Jahagirdar R, Johansson J, Sweeney M, Wong NC, Kulikowski E. Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208). J Cardiovasc Transl Res. 2017; 10(4): 337-347. [DOI: 10.1007/s12265-017-9755-z]; [PMID: 28567671]

24. Nicholls SJ, Gordon A, Johansson J, Wolski K, Ballantyne CM, Kastelein JJ, Taylor A, Borgman M, Nissen SE. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol. 2011; 57(9): 1111-9. [DOI: 10.1016/j.jacc.2010.11.015]; [PMID: 21255957]

25. McNeill E. RVX-208, a stimulator of apolipoprotein AI gene expression for the treatment of cardiovascular diseases. Curr Opin Investig Drugs. 2010; 11(3): 357-64. [PMID: 20178050]

26. Nicholls SJ, Puri R, Wolski K, Ballantyne CM, Barter PJ, Brewer HB, Kastelein JJ, Hu B, Uno K, Kataoka Y, Herrman JP, Merkely B, Borgman M, Nissen SE. Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial. Am J Cardiovasc Drugs. 2016; 16(1): 55-65. [DOI: 10.1007/s40256-015-0146-z]; [PMID: 26385396]

27. Shishikura D, Kataoka Y, Honda S, Takata K, Kim SW, Andrews J, Psaltis PJ, Sweeney M, Kulikowski E, Johansson J, Wong NCW, Nicholls SJ. The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial. Am J Cardiovasc Drugs. 2019; 19(1): 49-57. [DOI: 10.1007/s40256-018-0298-8]; [PMID: 30155718]

28. Nicholls SJ, Gordon A, Johannson J, Ballantyne CM, Barter PJ, Brewer HB, Kastelein JJ, Wong NC, Borgman MR, Nissen SE. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies. Cardiovasc Drugs Ther. 2012; 26: 181-187. [DOI: 10.1007/s10557-012-6373-5]; [PMID: 22349989]

29. Nicholls SJ, Ray KK, Johansson JO, Gordon A, Sweeney M, Halliday C, Kulikowski E, Wong N, Kim SW, Schwartz GG. Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease. Am J Cardiovasc Drugs. 2018; 8(2): 109-115. [DOI: 10.1007/s40256-017-0250-3]; [PMID: 29027131]

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