Research Article
BRD4 expression in patients with essential hypertension and its effect on blood pressure in spontaneously hypertensive rats

https://doi.org/10.1016/j.jash.2018.11.004Get rights and content

Highlights

  • BRD4 was highly expressed in patients with EH.

  • BRD4 expression was positively correlated to SBP and DBP of patients with EH.

  • BRD4 inhibitor JQ1 had a stable antihypertension effect on SHR rats.

  • Inhibiting BRD4 alleviated oxidative stress and inflammatory response in SHR rats.

Abstract

The objective of this study was to investigate BRD4 expression in patients with essential hypertension (EH) and its effects on the blood pressure in spontaneously hypertensive (SHR) rats. BRD4 expression was detected by quantitative real-time polymerase chain reaction and western blot in 163 patients with EH and its relation to systolic blood pressure and diastolic blood pressure were analyzed accordingly. In vivo, rats were divided into WKY (Wistar-Kyoto rats), SHR (spontaneously hypertensive rats), SHR + JQ1 (BRD4 inhibitor), and SHR + Vehicle control. Rats' blood pressure was measured by the tail-cuff method. The protein expressions related to inflammation and oxidative stress of rats were determined. BRD4 was higher in patients with EH than healthy controls, which was positively correlated to systolic blood pressure and diastolic blood pressure of enrolled subjects including patients with EH and healthy controls. Rats in the SHR group showed reduced food-intake, decreased body weight, and gradually increased blood pressure compared with WKY group. Besides, SHR rats were upregulated in plasma levels of Ang II, ET-1, MDA, IL-6, and TNF-α, and substantially downregulated in NO, NOS, and SOD levels. Moreover, eNOS activity in aortic tissues of SHR rats declined obviously, whereas the content of nitrite and O2, the activity of NADPH oxidase and NADH oxidase, and the expression of p-NF-κB p65 went up statistically, which could be partially reversed by JQ1. BRD4 was highly expressed in patients with EH, and inhibiting BRD4 could reduce oxidative stress and inflammatory response, alleviate endothelial cell damage, ameliorate aortic injury, and lower blood pressure, supporting the hypothesis that BRD4 inhibition could be a potential target for the clinical treatment of patients with EH.

Introduction

Hypertension is a very common cardiovascular disease and a major global public health problem, posing a great threat to human beings worldwide.1 Over one billion adults in the world are suffering from hypertension now, and as estimated, the number would be astoundingly risen to 1.56 billion by 2025.2, 3 Following 1999 World Health Organization/International Society of Hypertension hypertension guidelines for definition of elevated blood pressure, hypertension is defined as systolic blood pressure (SBP) over 140 mm Hg or diastolic blood pressure (DBP) over 90 mm Hg,4 and a variety of factors, such as age, gender, family history of hypertension, living environment, eating habits, and stress, can influence the development and progression of hypertension.2, 5, 6 Based on different pathogenesis, hypertension can be classified as essential hypertension (EH, also known as primary hypertension or spontaneous hypertension) and secondary hypertension, among which EH is the most common one and accounts for over 95% of hypertension.7 Although the traditional antihypertensive drugs are effective in lowering blood pressure, some of them would induce adverse effects.8, 9 Thus, it is imperative to find alternative therapeutic methods for hypertension prevention and treatment.

Bromodomain-containing protein 4 (BRD4) is one of the major members of the bromodomain and extra terminal domain (BET) family, and this family includes mammalian BRD2, BRD3, BRD4, and BRDT.10, 11 BRD4 is a chromatin “adapter” that binds to acetylated chromatin widely expressed in mammalian cells, which plays an essential role in many biological processes, including genome replication, gene transcription, cell cycle regulation, oncogenesis, and viral genome isolation.12, 13 In recent years, BRD4 has been found to greatly affect various cardiovascular diseases, for example, inhibiting BRD4-mediated NF-κB pathway could reduce the apoptosis of cardiac myocytes in myocardial infarction.14 Besides, remarkably enhanced BRD4 has been revealed in hypertrophic right ventricular by detecting the Sugen/hypoxia (SU-Hx) rat model with severe angioproliferative pulmonary hypertension.15 It is also worth mentioning that the microarray analysis in a previous study found the apparent upregulation of BRD4 in peripheral blood of patients with EH than in normal controls, suggesting the involvement of BRD4 in the occurrence and progression of EH. However, the BRD4 expression was not verified by quantitative real-time RT-PCR technique.16 In addition, there are few studies on the correlation between BRD4 and EH, and the corresponding mechanism has not been elucidated. Therefore, this study was performed to investigate the expression of BRD4 in patients with EH via clinical experiments and to explore the effect of inhibiting BRD4 on the blood pressure in spontaneously hypertensive (SHR) rats in vivo, hypothesizing that the inhibition of BRD4 may be a new therapeutic target for EH.

Section snippets

Ethics Statement

The selected subjects and performance of experiments in this study was approved by the Ethics Committee of Rizhao People's Hospital,17 and all patients signed the informed consent form before study. All animal experiments were also conducted according to local protocols on the care and use of laboratory animals, and in strict obedience to the Declaration of Helsinki.18

Study Subjects

From May 2016 to May 2018, 163 patients diagnosed and confirmed as EH in the Cardiovascular Department of Rizhao People's

General Information of Subjects in Control Group and Case Group

As shown in Table 1, there was no significant difference between the control group and the case group regarding age, gender, smoking, drinking, body mass index, heart rate, serum creatine, total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride (all P > .05). But in terms of SBP and DBP, patients in the case group were significantly higher than those healthy controls in the control group (all P < .001).

Comparison of BRD4 Expression in Control Group and Case Group

Compared with healthy individuals in the control group, patients in the case

Discussion

Cardiovascular diseases are a frequent cause of death also known as circulation system diseases, including hypertension, angina pectoris, acute myocardial infarction, coronary heart disease, heart failure, arrhythmia, and so on.24 Although as a transcriptional regulatory factor, BRD4 can affect downstream gene expressions by epigenetic regulation and thereby implicating in various cardiovascular-related diseases.12, 25 For example, BRD4 was reported to have a crucial role in heart failure

Acknowledgments

The authors would like to express their sincere appreciation to the reviewers for their comments on this study.

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    Conflict of interest: None.

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