Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function.

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

Circulation

journal_title

Circulation

authors

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 JA

doi

10.1161/CIRCULATIONAHA.120.047239

subject

Has Abstract

pub_date

2020-12-15 00:00:00

pages

2356-2370

issue

24

eissn

0009-7322

issn

1524-4539

journal_volume

142

pub_type

杂志文章
  • Differential effects of green tea-derived catechin on developing versus established atherosclerosis in apolipoprotein E-null mice.

    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

    authors: Chyu KY,Babbidge SM,Zhao X,Dandillaya R,Rietveld AG,Yano J,Dimayuga P,Cercek B,Shah PK

    更新日期:2004-05-25 00:00:00

  • Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.

    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

    authors: Heckbert SR,Hindorff LA,Edwards KL,Psaty BM,Lumley T,Siscovick DS,Tang Z,Durda JP,Kronmal RA,Tracy RP

    更新日期:2003-04-22 00:00:00

  • Cardiac Implantable Electronic Device Interrogation at Forensic Autopsy: An Underestimated Resource?

    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

    authors: Lacour P,Buschmann C,Storm C,Nee J,Parwani AS,Huemer M,Attanasio P,Boldt LH,Rauch G,Kucher A,Pieske B,Haverkamp W,Blaschke F

    更新日期:2018-06-19 00:00:00

  • Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, an

    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

    authors: Batchelor WB,Tolleson TR,Huang Y,Larsen RL,Mantell RM,Dillard P,Davidian M,Zhang D,Cantor WJ,Sketch MH Jr,Ohman EM,Zidar JP,Gretler D,DiBattiste PM,Tcheng JE,Califf RM,Harrington RA

    更新日期:2002-09-17 00:00:00

  • Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.

    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

    authors: Yokoe T,Minoguchi K,Matsuo H,Oda N,Minoguchi H,Yoshino G,Hirano T,Adachi M

    更新日期:2003-03-04 00:00:00

  • Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials.

    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

    authors: Chew DP,Bhatt DL,Lincoff AM,Moliterno DJ,Brener SJ,Wolski KE,Topol EJ

    更新日期:2001-02-20 00:00:00

  • Molecular genetics of lipoprotein disorders.

    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

    authors: Breslow JL

    更新日期:1984-06-01 00:00:00

  • Myocardial inotropic responses to aggregating platelets and modulation by the endocardium.

    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

    authors: Shah AM,Meulemans AL,Brutsaert DL

    更新日期:1989-06-01 00:00:00

  • Near drowning.

    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:

    authors: Modell JH

    更新日期:1986-12-01 00:00:00

  • Severe pulmonary hypertension associated with a small ventricular septal defect.

    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

    authors: Bisset GS 3rd,Hirschfeld SS

    更新日期:1983-02-01 00:00:00

  • Targeted deletion of Fgl-2/fibroleukin in the donor modulates immunologic response and acute vascular rejection in cardiac xenografts.

    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

    authors: Mendicino M,Liu M,Ghanekar A,He W,Koscik C,Shalev I,Javadi M,Turnbull J,Chen W,Fung L,Sakamoto S,Marsden P,Waddell TK,Phillips MJ,Gorczynski R,Levy GA,Grant D

    更新日期:2005-07-12 00:00:00

  • Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling.

    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

    authors: Wilson EM,Moainie SL,Baskin JM,Lowry AS,Deschamps AM,Mukherjee R,Guy TS,St John-Sutton MG,Gorman JH 3rd,Edmunds LH Jr,Gorman RC,Spinale FG

    更新日期:2003-06-10 00:00:00

  • Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping.

    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

    authors: Rebergen SA,Chin JG,Ottenkamp J,van der Wall EE,de Roos A

    更新日期:1993-11-01 00:00:00

  • Hemodynamic and radionuclide effects of acute captopril therapy for heart failure: changes in left and right ventricular volumes and function at rest and during exercise.

    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

    authors: Massie B,Kramer BL,Topic N,Henderson SG

    更新日期:1982-06-01 00:00:00

  • Analysis of ventricular activation using surface electrocardiography to predict left ventricular reverse volumetric remodeling during cardiac resynchronization therapy.

    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

    authors: Sweeney MO,van Bommel RJ,Schalij MJ,Borleffs CJ,Hellkamp AS,Bax JJ

    更新日期:2010-02-09 00:00:00

  • Effects of aortopulmonary collaterals on cerebral cooling and cerebral metabolic recovery after circulatory arrest.

    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

    authors: Kirshbom PM,Skaryak LA,DiBernardo LR,Kern FH,Greeley WJ,Gaynor JW,Ungerleider RM

    更新日期:1995-11-01 00:00:00

  • Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation.

    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

    authors: Gilligan DM,Panza JA,Kilcoyne CM,Waclawiw MA,Casino PR,Quyyumi AA

    更新日期:1994-12-01 00:00:00

  • Outcomes of endovascular repair of ruptured descending thoracic aortic aneurysms.

    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

    authors: Jonker FH,Verhagen HJ,Lin PH,Heijmen RH,Trimarchi S,Lee WA,Moll FL,Athamneh H,Muhs BE

    更新日期:2010-06-29 00:00:00

  • Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice.

    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

    authors: Schober A,Bernhagen J,Thiele M,Zeiffer U,Knarren S,Roller M,Bucala R,Weber C

    更新日期:2004-01-27 00:00:00

  • Endothelial-to-mesenchymal transition in pulmonary hypertension.

    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

    authors: Ranchoux B,Antigny F,Rucker-Martin C,Hautefort A,Péchoux C,Bogaard HJ,Dorfmüller P,Remy S,Lecerf F,Planté S,Chat S,Fadel E,Houssaini A,Anegon I,Adnot S,Simonneau G,Humbert M,Cohen-Kaminsky S,Perros F

    更新日期:2015-03-17 00:00:00

  • Magnetic resonance jet velocity mapping in mitral and aortic valve stenosis.

    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

    authors: Kilner PJ,Manzara CC,Mohiaddin RH,Pennell DJ,Sutton MG,Firmin DN,Underwood SR,Longmore DB

    更新日期:1993-04-01 00:00:00

  • Relation between left coronary artery stenosis and regional left ventricular function.

    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

    authors: St John Sutton MG,Frye RL,Smith HC,Chesebro JH,Ritman EL

    更新日期:1978-09-01 00:00:00

  • Wolff-Parkinson-White syndrome. The problem, evaluation, and surgical correction.

    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

    authors: Gallagher JJ,Gilbert M,Svenson RH,Sealy WC,Kasell J,Wallace AG

    更新日期:1975-05-01 00:00:00

  • Changes in left ventricular segmental wall motion following randomization to medicine or surgery in patients with unstable angina.

    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:

    authors: Priest MF,Curry GC,Smith LR,Rogers WJ,Mantle JA,Rackley CE,Kouchoukos NT,Russell RO Jr

    更新日期:1978-09-01 00:00:00

  • Precordial ST-segment depression during acute inferior myocardial infarction: clinical, scintigraphic and angiographic correlations.

    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

    authors: Gibson RS,Crampton RS,Watson DD,Taylor GJ,Carabello BA,Holt ND,Beller GA

    更新日期:1982-10-01 00:00:00

  • Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging.

    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

    authors: Kooi ME,Cappendijk VC,Cleutjens KB,Kessels AG,Kitslaar PJ,Borgers M,Frederik PM,Daemen MJ,van Engelshoven JM

    更新日期:2003-05-20 00:00:00

  • Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease.

    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

    authors: Deloughery TG,Evans A,Sadeghi A,McWilliams J,Henner WD,Taylor LM Jr,Press RD

    更新日期:1996-12-15 00:00:00

  • Assessment of submaximal exercise capacity in patients with left ventricular assist devices.

    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:

    authors: Foray A,Williams D,Reemtsma K,Oz M,Mancini D

    更新日期:1996-11-01 00:00:00

  • Coronary events after arterial switch operation for transposition of the great arteries.

    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

    authors: Legendre A,Losay J,Touchot-Koné A,Serraf A,Belli E,Piot JD,Lambert V,Capderou A,Planche C

    更新日期:2003-09-09 00:00:00

  • Hemodynamic performance at rest and during exercise after aortic valve replacement: comparison of pulmonary autografts versus aortic homografts.

    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:

    authors: Laforest I,Dumesnil JG,Briand M,Cartier PC,Pibarot P

    更新日期:2002-09-24 00:00:00