Publications by authors named "Saptarsi M Haldar"

46 Publications

Myocardial Gene Expression Signatures in Human Heart Failure With Preserved Ejection Fraction.

Circulation 2021 Jan 29;143(2):120-134. Epub 2020 Oct 29.

Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (V.S.H., J.V., D.A.K., K.S.).

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes half of all HF but lacks effective therapy. Understanding of its myocardial biology remains limited because of a paucity of heart tissue molecular analysis.

Methods: We performed RNA sequencing on right ventricular septal endomyocardial biopsies prospectively obtained from patients meeting consensus criteria for HFpEF (n=41) contrasted with right ventricular septal tissue from patients with HF with reduced ejection fraction (HFrEF, n=30) and donor controls (n=24). Principal component analysis and hierarchical clustering tested for transcriptomic distinctiveness between groups, effect of comorbidities, and differential gene expression with pathway enrichment contrasted HF groups and donor controls. Within HFpEF, non-negative matrix factorization and weighted gene coexpression analysis identified molecular subgroups, and the resulting clusters were correlated with hemodynamic and clinical data.

Results: Patients with HFpEF were more often women (59%), African American (68%), obese (median body mass index 41), and hypertensive (98%), with clinical HF characterized by 65% New York Heart Association Class III or IV, nearly all on a loop diuretic, and 70% with a HF hospitalization in the previous year. Principal component analysis separated HFpEF from HFrEF and donor controls with minimal overlap, and this persisted after adjusting for primary comorbidities: body mass index, sex, age, diabetes, and renal function. Hierarchical clustering confirmed group separation. Nearly half the significantly altered genes in HFpEF versus donor controls (1882 up, 2593 down) changed in the same direction in HFrEF; however, 5745 genes were uniquely altered between HF groups. Compared with controls, uniquely upregulated genes in HFpEF were enriched in mitochondrial adenosine triphosphate synthesis/electron transport, pathways downregulated in HFrEF. HFpEF-specific downregulated genes engaged endoplasmic reticulum stress, autophagy, and angiogenesis. Body mass index differences largely accounted for HFpEF upregulated genes, whereas neither this nor broader comorbidity adjustment altered pathways enriched in downregulated genes. Non-negative matrix factorization identified 3 HFpEF transcriptomic subgroups with distinctive pathways and clinical correlates, including a group closest to HFrEF with higher mortality, and a mostly female group with smaller hearts and proinflammatory signaling. These groupings remained after sex adjustment. Weighted gene coexpression analysis yielded analogous gene clusters and clinical groupings.

Conclusions: HFpEF exhibits distinctive broad transcriptomic signatures and molecular subgroupings with particular clinical features and outcomes. The data reveal new signaling targets to consider for precision therapeutics.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856095PMC
January 2021

BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes.

Circulation 2020 Dec 23;142(24):2338-2355. Epub 2020 Oct 23.

Gladstone Institute of Cardiovascular Disease, San Francisco, CA (A.P., M.A., B.G.-T., Y.H., A.H., Q.D., S.A.B.W., F.F., J.A.P.-B., S.M.H., D.S.).

Background: Gene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown.

Methods: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis.

Results: Here, we show that cardiomyocyte-specific deletion of in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators , and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity.

Conclusions: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736290PMC
December 2020

BETs that cover the spread from acquired to heritable heart failure.

J Clin Invest 2020 09;130(9):4536-4539

Gladstone Institutes, San Francisco, California, USA.

Heart failure (HF) with reduced contractile function is a common and lethal syndrome in which the heart cannot pump blood to adequately meet bodily demands, resulting in high mortality despite the current standard of care. In modern societies, the most common drivers of HF are ischemic heart disease and hypertension. However, in a substantial subset of cases, patients present with dilated and poorly contracting hearts without evidence of common inciting stressors, a syndrome called dilated cardiomyopathy (DCM). Genome sequencing has identified a host of deleterious germline variants in key cardiomyocyte genes as causes of heritable DCM, including mutations in LMNA, which encodes the nuclear lamina-associated protein lamin A/C. In this issue of the JCI, Auguste et al. generate a mouse model of DCM in which they delete Lmna in cardiomyocytes and discover that bromodomain and extraterminal (BET) protein activation is a druggable epigenetic mechanism of disease pathogenesis in this heritable HF syndrome.
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http://dx.doi.org/10.1172/JCI140304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456232PMC
September 2020

A New Therapeutic Framework for Atrial Fibrillation Drug Development.

Circ Res 2020 06 18;127(1):184-201. Epub 2020 Jun 18.

Bayer AG, Pharma-RD-PCR TA Cardiovascular Disease, Wuppertal, Germany (J.H.).

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia and cause of significant morbidity and mortality. Its increasing prevalence in aging societies constitutes a growing challenge to global healthcare systems. Despite substantial unmet needs in AF prevention and treatment, drug developments hitherto have been challenging, and the current pharmaceutical pipeline is nearly empty. In this review, we argue that current drugs for AF are inadequate because of an oversimplified system for patient classification and the development of drugs that do not interdict underlying disease mechanisms. We posit that an improved understanding of AF molecular pathophysiology related to the continuous identification of novel disease-modifying drug targets and an increased appreciation of patient heterogeneity provide a new framework to personalize AF drug development. Together with recent innovations in diagnostics, remote rhythm monitoring, and big data capabilities, we anticipate that adoption of a new framework for patient subsegmentation based on pathophysiological, genetic, and molecular subsets will improve success rates of clinical trials and advance drugs that reduce the individual patient and public health burden of AF.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316576DOI Listing
June 2020

BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Emory University School of Medicine, Atlanta, Georgia, USA.

The bromodomain and extraterminal (BET) family comprises epigenetic reader proteins that are important regulators of inflammatory and hypertrophic gene expression in the heart. We previously identified the activation of proinflammatory gene networks as a key early driver of dilated cardiomyopathy (DCM) in transgenic mice expressing a mutant form of phospholamban (PLNR9C) - a genetic cause of DCM in humans. We hypothesized that BETs coactivate this inflammatory process, representing a critical node in the progression of DCM. To test this hypothesis, we treated PLNR9C or age-matched WT mice longitudinally with the small molecule BET bromodomain inhibitor JQ1 or vehicle. BET inhibition abrogated adverse cardiac remodeling, reduced cardiac fibrosis, and prolonged survival in PLNR9C mice by inhibiting expression of proinflammatory gene networks at all stages of disease. Specifically, JQ1 had profound effects on proinflammatory gene network expression in cardiac fibroblasts, while having little effect on gene expression in cardiomyocytes. Cardiac fibroblast proliferation was also substantially reduced by JQ1. Mechanistically, we demonstrated that BRD4 serves as a direct and essential regulator of NF-κB-mediated proinflammatory gene expression in cardiac fibroblasts. Suppressing proinflammatory gene expression via BET bromodomain inhibition could be a novel therapeutic strategy for chronic DCM in humans.
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http://dx.doi.org/10.1172/jci.insight.138687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455078PMC
August 2020

Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling.

J Clin Invest 2020 06;130(6):2966-2977

Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes, San Francisco, California, USA.

Salt-inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and heart failure pathogenesis remains unknown. Here, we showed that loss of SIK1 kinase activity protected against adverse cardiac remodeling and heart failure pathogenesis in rodent models and cardiomyocytes derived from human induced pluripotent stem cells. We found that SIK1 phosphorylated and stabilized histone deacetylase 7 (HDAC7) protein during cardiac stress, an event that is required for pathologic cardiomyocyte remodeling. Gain- and loss-of-function studies of HDAC7 in cultured cardiomyocytes implicated HDAC7 as a prohypertrophic signaling effector that can induce c-Myc expression, indicating a functional departure from the canonical MEF2 corepressor function of class IIa HDACs. Taken together, our findings reveal what we believe to be a previously unrecognized role for a SIK1/HDAC7 axis in regulating cardiac stress responses and implicate this pathway as a potential target in human heart failure.
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http://dx.doi.org/10.1172/JCI133753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259992PMC
June 2020

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University (NU), Chicago, Illinois, USA.

In humans, chronic glucocorticoid use is associated with side effects like muscle wasting, obesity, and metabolic syndrome. Intermittent steroid dosing has been proposed in Duchenne Muscular Dystrophy patients to mitigate the side effects seen with daily steroid intake. We evaluated biomarkers from Duchenne Muscular Dystrophy patients, finding that, compared with chronic daily steroid use, weekend steroid use was associated with reduced serum insulin, free fatty acids, and branched chain amino acids, as well as reduction in fat mass despite having similar BMIs. We reasoned that intermittent prednisone administration in dystrophic mice would alter muscle epigenomic signatures, and we identified the coordinated action of the glucocorticoid receptor, KLF15 and MEF2C as mediators of a gene expression program driving metabolic reprogramming and enhanced nutrient utilization. Muscle lacking Klf15 failed to respond to intermittent steroids. Furthermore, coadministration of the histone acetyltransferase inhibitor anacardic acid with steroids in mdx mice eliminated steroid-specific epigenetic marks and abrogated the steroid response. Together, these findings indicate that intermittent, repeated exposure to glucocorticoids promotes performance in dystrophic muscle through an epigenetic program that enhances nutrient utilization.
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http://dx.doi.org/10.1172/jci.insight.132402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975267PMC
December 2019

Minimal requirements for developmentally regulated cardiac long intergenic non-coding RNAs.

Development 2019 12 9;146(23). Epub 2019 Dec 9.

Gladstone Institutes, San Francisco, CA 94158, USA

Long intergenic non-coding RNAs (lincRNAs) have been implicated in gene regulation, but their requirement for development needs empirical interrogation. We computationally identified nine murine lincRNAs that have developmentally regulated transcriptional and epigenomic profiles specific to early heart differentiation. Six of the nine lincRNAs had expression patterns supporting a potential function in heart development, including a transcript downstream of the cardiac transcription factor , which we named (-associated lincRNA), and We genetically ablated these six lincRNAs in mouse, which suggested genomic regulatory roles for four of the cohort. However, none of the lincRNA deletions led to severe cardiac phenotypes. Thus, we stressed the hearts of adult and mutant mice by transverse aortic banding and found that absence of these lincRNAs did not affect cardiac hypertrophy or left ventricular function post-stress. Our results support roles for lincRNA transcripts and/or transcription in the regulation of topologically associated genes. However, the individual importance of developmentally specific lincRNAs is yet to be established. Their status as either gene-like entities or epigenetic components of the nucleus should be further considered.
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http://dx.doi.org/10.1242/dev.185314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918742PMC
December 2019

Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation.

Circ Res 2019 09 14;125(7):662-677. Epub 2019 Aug 14.

From the Department of Medicine, Division of Cardiology (M.S.S., R.A.B., M.B.F., A.S.R., B.Y.E., K.A.K., M.A.C., K.S., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.

Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown.

Objective: We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart.

Methods And Results: RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-β (transforming growth factor-β) signaling to stimulate conversion of quiescent cardiac fibroblasts into ()-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for in TGF-β-mediated cardiac fibroblast activation.

Conclusions: These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for . The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310347PMC
September 2019

Epigenetic therapies in heart failure.

J Mol Cell Cardiol 2019 05 13;130:197-204. Epub 2019 Apr 13.

Gladstone Institutes, San Francisco, CA, United States of America; Division of Cardiology, Department of Medicine, University of California San Francisco School of Medicine, San Francisco, CA, United States of America; Cardiometabolic Disorders, Amgen, South San Francisco, CA, United States of America. Electronic address:

Heart failure (HF) is a dominant cause of morbidity and mortality in the developed world, with available pharmacotherapies limited by high rates of residual mortality and a failure to directly target the changes in cell state that drive adverse cardiac remodeling. Pathologic cardiac remodeling is driven by stress-activated cardiac signaling cascades that converge on defined components of the chromatin regulatory apparatus in the nucleus, triggering broad shifts in transcription and cell state. Thus, studies focusing on how cytosolic signaling pathways couple to the nuclear gene control machinery has been an area of therapeutic interest in HF. In this review, we discuss current concepts pertaining to the role of chromatin regulators in HF pathogenesis, with a focus on specific proteins and RNA-containing macromolecular complexes that have shown promise as druggable targets in the experimental setting.
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http://dx.doi.org/10.1016/j.yjmcc.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850768PMC
May 2019

Drugging transcription in heart failure.

J Physiol 2020 07 23;598(14):3005-3014. Epub 2019 Apr 23.

Division of Cardiology, Department of Medicine, University of California San Francisco School of Medicine, San Francisco, CA, USA.

Advances in our understanding of the basic biology and biochemistry of chromatin structure and function at genome scales has led to tremendous growth in the fields of epigenomics and transcriptional biology. While it has long been appreciated that transcriptional pathways are dysregulated in failing hearts, only recently has the idea of disrupting altered transcription by targeting chromatin-associated proteins been explored. Here, we provide a brief overview of efforts to drug transcription in the context of heart failure, focusing on the bromo- and extra-terminal domain (BET) family of chromatin co-activator proteins.
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http://dx.doi.org/10.1113/JP276745DOI Listing
July 2020

Unusual transcription factor protects against heart failure.

Science 2018 12;362(6421):1359-1360

Gladstone Institutes, San Francisco, CA, USA.

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http://dx.doi.org/10.1126/science.aav8956DOI Listing
December 2018

The Cardiac Myofibroblast.

Circ Res 2018 12;123(12):1258-1260

From the Gladstone Institutes, San Francisco, CA (M.A., S.M.H.).

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http://dx.doi.org/10.1161/CIRCRESAHA.118.314185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453134PMC
December 2018

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.

EBioMedicine 2018 May 4;31:226-242. Epub 2018 May 4.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address:

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn;SMN2 and Smn mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013932PMC
May 2018

BET bromodomain proteins regulate enhancer function during adipogenesis.

Proc Natl Acad Sci U S A 2018 02 14;115(9):2144-2149. Epub 2018 Feb 14.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of and , thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the locus by CRISPRi demonstrates a critical role for these enhancers in the control of gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.
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http://dx.doi.org/10.1073/pnas.1711155115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834672PMC
February 2018

Plasma MicroRNA Clusters in Human Left Ventricular Remodeling: A Biomarker and Discovery Platform.

Circ Heart Fail 2018 02;11(2):e004793

From the Division of Cardiology, Department of Medicine, University of California San Francisco School of Medicine; and Gladstone Institute of Cardiovascular Disease, San Francisco, CA.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813833PMC
February 2018

Probing the Pathogenesis of Duchenne Muscular Dystrophy Using Mouse Models.

Methods Mol Biol 2018 ;1687:107-119

Gladstone Institutes, 1650 Owens Street, San Francisco, CA, 94158, USA.

Investigations using mouse models have provided seminal insights into the pathogenesis of Duchenne muscular dystrophy and the development of novel therapeutics. Several important methods have been considered standard-in-the-field for analyses of skeletal muscle weakness, strength, endurance, and histopathology, as well as responses to therapeutics such as glucocorticoids, disease modifying drugs which are part of the current standard of care for patients with this disease. Here we describe optimized genetic, genomic, and physiologic assays to probe dystrophic pathobiology in the mdx mouse and related strains.
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http://dx.doi.org/10.1007/978-1-4939-7374-3_8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805135PMC
June 2018

BRD4 inhibition for the treatment of pathological organ fibrosis.

F1000Res 2017 28;6. Epub 2017 Jun 28.

Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

Fibrosis is defined as excess deposition of extracellular matrix, resulting in tissue scarring and organ dysfunction. It is estimated that 45% of deaths in the developed world are due to fibrosis-induced organ failure. Despite the well-accepted role of fibrosis in the pathogenesis of numerous diseases, there are only two US Food and Drug Administration-approved anti-fibrotic therapies, both of which are currently restricted to the treatment of pulmonary fibrosis. Thus, organ fibrosis represents a massive unmet medical need. Here, we review recent findings suggesting that an epigenetic regulatory protein, BRD4, is a nodal effector of organ fibrosis, and we highlight the potential of small-molecule BRD4 inhibitors for the treatment of diverse fibrotic diseases.
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http://dx.doi.org/10.12688/f1000research.11339.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497817PMC
June 2017

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.

Sci Transl Med 2017 05;9(390)

Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.
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http://dx.doi.org/10.1126/scitranslmed.aah5084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544253PMC
May 2017

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.

Cell Rep 2016 08 14;16(5):1366-1378. Epub 2016 Jul 14.

Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Medical Scientist Training Program, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3' UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.
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http://dx.doi.org/10.1016/j.celrep.2016.06.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972677PMC
August 2016

Sarcomeres and Cardiac Growth: Tension in the Relationship.

Trends Mol Med 2016 07 26;22(7):530-533. Epub 2016 May 26.

Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Pediatrics, Division of Cardiology, UCSF School of Medicine, San Francisco, CA 94143, USA. Electronic address:

Genetic mutations in the cardiomyocyte contractile apparatus cause aberrant cardiac growth categorized morphologically as hypertrophic or dilated. A recent study leverages an array of mutant mouse models to extrapolate a new integrated parameter: the myofilament 'tension index', which predicts patterns of cardiac growth resulting from individual sarcomeric mutations. These findings may inform genotype-specific therapies.
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http://dx.doi.org/10.1016/j.molmed.2016.05.001DOI Listing
July 2016

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.

Proc Natl Acad Sci U S A 2015 Dec 23;112(49):E6780-9. Epub 2015 Nov 23.

Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Gladstone Institutes, San Francisco, CA 94158; Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106; Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94158

Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
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http://dx.doi.org/10.1073/pnas.1512968112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679037PMC
December 2015

Megamitochondria in Cardiomyocytes of a Knockout (Klf15-/-) Mouse.

Ultrastruct Pathol 2015 25;39(5):336-9. Epub 2015 Jun 25.

e Case Cardiovascular Research Institute, School of Medicine, Case Western Reserve University , Cleveland , OH , USA , and.

The Kruppel-like factors (KLF) family of zinc-finger transcriptional regulators control many aspects of cardiomyocyte structure and function. Deletion of Klf15 from the nuclear genome in mice affects cardiac mitochondria. Some become grossly enlarged, extending many sarcomeres in length. These display many sites of incipient pinching, but there is little attenuation of the megamitochondria at these sites; there are no examples of organelles that clearly have reached the point where further membrane encroachment will cause separation into smaller daughter mitochondria. It is clear that deletion of Klf15 interferes with nuclear control of mitochondrial fission, whereas fusion appears to be unaffected.
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http://dx.doi.org/10.3109/01913123.2015.1042610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827860PMC
July 2016

Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.

Circ Res 2015 Jul 1;117(2):166-77. Epub 2015 Jun 1.

From the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).

Rationale: Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.

Objective: Determine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene.

Methods And Results: Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.

Conclusions: This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.306666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758452PMC
July 2015

Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning.

J Mol Cell Cardiol 2015 Mar 7;80:114-25. Epub 2015 Jan 7.

Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA; Marshall Institute for Interdisciplinary Research, Huntington, WV, USA. Electronic address:

Acute myocardial infarction, the clinical manifestation of ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of ischemia and reperfusion, ouabain preconditioning (OPC) mediated by Na/K-ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4 min of ouabain 10 μM and IPC was triggered by 4 cycles of 5 min ischemia and reperfusion prior to 40 min of global ischemia and 30 min of reperfusion. Without affecting PI3K-IB, ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser(473). IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced lactate dehydrogenase release, and decreased infarct size. OPC protection was blunted by the PI3K-IA inhibitor PI-103, but not by the PI3K-IB inhibitor AS-604850. In contrast, IPC-mediated protection was not affected by PI-103 but was blocked by AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways.
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http://dx.doi.org/10.1016/j.yjmcc.2014.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827870PMC
March 2015

Neuroprotection in ischemic stroke: AhR we making progress?

Circulation 2014 Dec 30;130(23):2002-4. Epub 2014 Oct 30.

From the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.P.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH (S.M.H.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.013533DOI Listing
December 2014

Epigenetic mechanisms in heart failure pathogenesis.

Circ Heart Fail 2014 Sep;7(5):850-863

Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.114.001193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169025PMC
September 2014

BET-ting on chromatin-based therapeutics for heart failure.

J Mol Cell Cardiol 2014 Sep 14;74:98-102. Epub 2014 May 14.

Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

Studies of transcriptional mechanisms in heart failure have focused heavily on roles of sequence-specific DNA-binding factors such as NFAT, MEF2 and GATA4. Recent findings have illuminated crucial functions for epigenetic regulators in the control of cardiac structural remodeling and mechanical dysfunction in response to pathological stress. Here, we review the current understanding of chromatin-dependent signal transduction in cardiac gene control, and highlight the potential for pharmacologic regulation of BET acetyl-lysine binding proteins as a means of treating heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2014.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115033PMC
September 2014

Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.

J Biol Chem 2014 Feb 8;289(9):5914-24. Epub 2014 Jan 8.

From the Case Cardiovascular Research Institute and Harrington Heart and Vascular Institute.

The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism.
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http://dx.doi.org/10.1074/jbc.M113.531384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937660PMC
February 2014

BET bromodomains mediate transcriptional pause release in heart failure.

Cell 2013 Aug;154(3):569-82

Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.

Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.
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http://dx.doi.org/10.1016/j.cell.2013.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090947PMC
August 2013