Abstract:
BACKGROUND:BET (bromodomain and extraterminal) epigenetic reader proteins, in particular BRD4 (bromodomain-containing protein 4), have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small-molecule BET protein inhibitors such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BET proteins in the heart have not been conducted to validate pharmacological findings and to unveil potential pharmacological side effects. METHODS:By engineering a cardiomyocyte-specific BRD4 knockout mouse, we investigated the role of BRD4 in cardiac pathophysiology. We performed functional, transcriptomic, and mitochondrial analyses to evaluate BRD4 function in developing and mature hearts. RESULTS:Unlike pharmacological inhibition, loss of BRD4 protein triggered progressive declines in myocardial function, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse heart tissue identified early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria from these hearts confirmed that BRD4 ablation triggered significant changes in mitochondrial electron transport chain protein expression and activity. Computational analysis identified candidate transcription factors participating in the BRD4-regulated transcriptome. In particular, estrogen-related receptor α, a key nuclear receptor in metabolic gene regulation, was enriched in promoters of BRD4-regulated mitochondrial genes. CONCLUSIONS:In aggregate, we describe a previously unrecognized role for BRD4 in regulating cardiomyocyte mitochondrial homeostasis, observing that its function is indispensable to the maintenance of normal cardiac function.
journal_name
Circulationjournal_title
Circulationauthors
Kim SY,Zhang X,Schiattarella GG,Altamirano F,Ramos TAR,French KM,Jiang N,Szweda PA,Evers BM,May HI,Luo X,Li H,Szweda LI,Maracaja-Coutinho V,Lavandero S,Gillette TG,Hill JAdoi
10.1161/CIRCULATIONAHA.120.047239subject
Has Abstractpub_date
2020-12-15 00:00:00pages
2356-2370issue
24eissn
0009-7322issn
1524-4539journal_volume
142pub_type
杂志文章相关文献
CIRCULATION文献大全abstract:BACKGROUND:Oxidative stress has been implicated in vascular injury and atherogenesis, and antioxidant treatment has shown favorable results in preclinical studies. Despite this, antioxidant therapy has failed to show benefit in clinical trials. Failure of antioxidants in clinical trials may be partly because such thera...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000128034.70732.C2
更新日期:2004-05-25 00:00:00
abstract:BACKGROUND:Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study. METHODS AND RESULTS:A total of 808 black and 4441 whi...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000065231.07729.92
更新日期:2003-04-22 00:00:00
abstract:BACKGROUND:Postmortem interrogations of cardiac implantable electronic devices (CIEDs), recommended at autopsy in suspected cases of sudden cardiac death, are rarely performed, and data on systematic postmortem CIED analysis in the forensic pathology are missing. The aim of the study was to determine whether nonselecti...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.117.032367
更新日期:2018-06-19 00:00:00
abstract:BACKGROUND:The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS:We randomized 70 acute coronary syndrome patients undergoing percu...
journal_title:Circulation
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1161/01.cir.0000029744.01096.1f
更新日期:2002-09-17 00:00:00
abstract:BACKGROUND:C-reactive protein (CRP) and interleukin (IL)-6 are important risk factors for atherosclerosis and coronary heart disease. In the present study, we examined serum levels of CRP and IL-6, IL-6 production by monocytes, and the effect of nasal continuous positive airway pressure (nCPAP) in patients with obstruc...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.0000052627.99976.18
更新日期:2003-03-04 00:00:00
abstract:BACKGROUND:Unfractionated heparin has been the primary anticoagulant therapy for percutaneous coronary intervention for >20 years. Despite the availability of rapid "point of care" testing, little clinical data defining the optimal level of anticoagulation are available. Furthermore, recent reports have advocated the u...
journal_title:Circulation
pub_type: 杂志文章,meta分析
doi:10.1161/01.cir.103.7.961
更新日期:2001-02-20 00:00:00
abstract::These types of studies lay the foundation for understanding the human apolipoproteins at the genetic level. In addition, through a few specific examples, we have already shown evidence at the DNA level that lesions in apolipoprotein genes can play a role in human atherosclerosis. This work is in its infancy, but we ho...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.69.6.1190
更新日期:1984-06-01 00:00:00
abstract::Ventricular mural thrombi complicate many cardiac diseases. The endocardial endothelium can modulate the mechanical performance of subjacent myocardium and mediate responses to certain physiopharmacologic agents. We studied the effects of aggregating platelets on the contractile performance of isolated cardiac muscle....
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.79.6.1315
更新日期:1989-06-01 00:00:00
abstract::Several conditions that contribute to drowning and near drowning must be considered in the treatment of near-drowned victims. Regardless of the cause, mechanical ventilation should begin as soon as possible and closed-chest cardiac massage should be administered when there is any question about the adequacy of cardiac...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::A case of progressive pulmonary hypertension in a child with a small ventricular septal defect is presented. Natural history studies have indicated that children with small ventricular septal defects can be followed conservatively. This case represents a contradiction to that rule and suggests that further study must ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.67.2.470
更新日期:1983-02-01 00:00:00
abstract:BACKGROUND:Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. METHODS AND RESULTS:We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2-/-) in the ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.105.534271
更新日期:2005-07-12 00:00:00
abstract:BACKGROUND:Induction of matrix metalloproteinases (MMPs) contributes to adverse remodeling after myocardial infarction (MI). Whether a region- and type-specific distribution of MMPs occurs within the post-MI myocardium remained unknown. METHODS AND RESULTS:Ten sheep were instrumented with a sonomicrometry array to mea...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000068375.40887.FA
更新日期:2003-06-10 00:00:00
abstract:BACKGROUND:Pulmonary regurgitation frequently occurs after surgical correction of tetralogy of Fallot. To date, reliable quantitation of pulmonary regurgitation has not been possible, and therefore the clinical significance of pulmonary regurgitation is controversial. Nuclear magnetic resonance (NMR) velocity mapping a...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.88.5.2257
更新日期:1993-11-01 00:00:00
abstract::Although the resting hemodynamic effects of captopril in congestive heart failure are known, little information is available about the hemodynamic response to captopril during exercise or about changes in noninvasive measurements of the size and function of both ventricles. In this study, 14 stable New York Heart Asso...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.65.7.1374
更新日期:1982-06-01 00:00:00
abstract:BACKGROUND:Cardiac resynchronization therapy for heart failure with left bundle branch block reduces left ventricular (LV) conduction delay, contraction asynchrony, and LV end-systolic volume ("reverse remodeling"). Up to one third of patients do not improve, and the electric requirements for reverse remodeling are unc...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.109.894774
更新日期:2010-02-09 00:00:00
abstract:BACKGROUND:Aortopulmonary collaterals (APC) have been associated with an increased risk of choreoathetosis after deep hypothermic circulatory arrest (DHCA). To study the effects of APC on cerebral hemodynamics and metabolism before and after DHCA, a piglet model was developed. METHODS AND RESULTS:Protocol 1: Eight 4- ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.92.9.490
更新日期:1995-11-01 00:00:00
abstract:BACKGROUND:Endothelium-derived nitric oxide is an important modulator of resting vascular tone in animals and humans. However, the contribution of nitric oxide to exercise-induced vasodilation is unknown. METHODS AND RESULTS:The effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on ex...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.90.6.2853
更新日期:1994-12-01 00:00:00
abstract:BACKGROUND:Thoracic endovascular aortic repair offers a less invasive approach for the treatment of ruptured descending thoracic aortic aneurysms (rDTAA). Due to the low incidence of this life-threatening condition, little is known about the outcomes of endovascular repair of rDTAA and the factors that affect these out...
journal_title:Circulation
pub_type: 杂志文章,多中心研究
doi:10.1161/CIRCULATIONAHA.109.908871
更新日期:2010-06-29 00:00:00
abstract:BACKGROUND:Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. METHODS AND RESULTS:We studied the role of MIF on neointima lesion formation after ...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.CIR.0000109201.72441.09
更新日期:2004-01-27 00:00:00
abstract:BACKGROUND:The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle a...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/CIRCULATIONAHA.114.008750
更新日期:2015-03-17 00:00:00
abstract:BACKGROUND:Magnetic resonance (MR) phase-shift velocity mapping is an established method for measurement of nonturbulent intravascular flow. Shortening the echo time of the MR sequence to 3.6 msec allowed application of the technique to turbulent jet flow. The objective of this study was validation of MR jet velocity m...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.87.4.1239
更新日期:1993-04-01 00:00:00
abstract::The effect of stenosis of the left main and proximal anterior descending coronary arteries on anterior left ventricular wall dynamics was investigated in 70 patients with ischemic heart disease by the use of roentgen videometric analysis of left ventricular angiograms. In all patients with ischemic heart disease, mean...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.58.3.491
更新日期:1978-09-01 00:00:00
abstract::Physiological studies of the type we have described, when performed in patients with the WPW syndrome, can yield diagnostic information regarding the mechanism of arrhythmia, demonstrate functional properties of therapeutic import, facilitate therapeutic decision-making about drug regimens and presumptively localize t...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.51.5.767
更新日期:1975-05-01 00:00:00
abstract::Twenty-six patients with unstable angina pectoris had biplane left ventricular (LV) angiograms and coronary arteriograms (CAGs) initially and at a median of 1 year following randomization to medical (15 patients) or surgical 11 patients) therapy. Left ventricular segmental wall motion was analyzed by a digital compute...
journal_title:Circulation
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1978-09-01 00:00:00
abstract::The cause and associated pathophysiology of precordial ST-segment depression (ST decreases) during acute inferior myocardial infarction (IMI) are controversial. To investigate this problem, electrocardiographic findings in 48 consecutive patients with acute IMI were prospectively compared with results of coronary angi...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.66.4.732
更新日期:1982-10-01 00:00:00
abstract:BACKGROUND:One of the features of high-risk atherosclerotic plaques is a preponderance of macrophages. Experimental studies with hyperlipidemic rabbits have shown that ultrasmall superparamagnetic particles of iron oxide (USPIOs) accumulate in plaques with a high macrophage content and that this induces magnetic resona...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.CIR.0000068315.98705.CC
更新日期:2003-05-20 00:00:00
abstract:BACKGROUND:Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this m...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:10.1161/01.cir.94.12.3074
更新日期:1996-12-15 00:00:00
abstract:BACKGROUND:Long-term implantable left ventricular assist devices (LVADs) are increasingly used as a bridge to cardiac transplantation and may be used as long-term therapy for end-stage heart failure. After insertion of an LVAD, patients frequently become ambulatory. Sensors contained within these devices can measure th...
journal_title:Circulation
pub_type: 杂志文章
doi:
更新日期:1996-11-01 00:00:00
abstract:BACKGROUND:Transfer of the coronary arteries is a crucial step during the arterial switch operation (ASO) for transposition of the great arteries. This retrospective study aims to assess the incidence and risk factors of coronary events after ASO and sensitivity of noninvasive tests in the diagnosis of the coronary obs...
journal_title:Circulation
pub_type: 杂志文章
doi:10.1161/01.cir.0000087902.67220.2b
更新日期:2003-09-09 00:00:00
abstract:BACKGROUND:The Ross procedure and aortic homografts have both been shown to have superior hemodynamic performance after valve replacement, but there have been few comparisons. METHODS:Sequential Doppler echocardiograms were performed up to 5 years after aortic valve replacement in 132 patients with the Ross procedure ...
journal_title:Circulation
pub_type: 临床试验,杂志文章
doi:
更新日期:2002-09-24 00:00:00