Research ArticleBRD4 expression in patients with essential hypertension and its effect on blood pressure in spontaneously hypertensive rats
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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2020, Histone Modifications in TherapyBRD4 contributes to high-glucose-induced podocyte injury by modulating Keap1/Nrf2/ARE signaling
2019, BiochimieCitation Excerpt :Therefore, our study suggests that BRD4 inhibition also exerts its cytoprotective function in the podocytes. BRD4 has emerged as a critical regulator for oxidative stress [31,32]. Interestingly, the antioxidant effect of BRD4 inhibition is associated with potentiation of Nrf2 antioxidant signaling.
Epigenetics and vascular diseases
2019, Journal of Molecular and Cellular CardiologyCitation Excerpt :It should be noted that HDAC mediated regulation of hypertension appears to be model specific, as others have not found HDACi mediated effects on blood pressure (e.g. [73]). Like other vascular pathologies mentioned above where HDAC inhibition and BET inhibition tend to have similar beneficial effects, BET inhibition with JQ1 potently reduced systolic and diastolic pressures in spontaneously hypertensive rats, while also reducing NF-ҡB signalling [151]. Though it is still not entirely clear why inhibition of deacetylases and inhibition of acetyl lysine reader proteins tend to result in similar effects, two scenarios dominate speculation in the field.
Conflict of interest: None.