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

Science Translational Medicine
Qiming DuanSaptarsi M Haldar

Abstract

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 transcripti...Continue Reading

References

Jul 14, 1988·The New England Journal of Medicine·M A PfefferE Braunwald
Dec 17, 2002·Experimental Physiology·Fang YangOscar A Carretero
Mar 15, 2005·The Journal of Clinical Investigation·Timothy A McKinsey, Eric N Olson
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Sep 6, 2006·Circulation·Sridhar HannenhalliThomas P Cappola
Aug 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Dwayne A BisgroveEric Verdin
Mar 28, 2008·The New England Journal of Medicine·Joseph A Hill, Eric N Olson
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Apr 9, 2010·Science Translational Medicine·Saptarsi M HaldarMukesh K Jain
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Oct 29, 2010·Genome Biology·Simon Anders, Wolfgang Huber
Nov 10, 2010·Journal of Molecular and Cellular Cardiology·Marcin DobaczewskiNikolaos G Frangogiannis
Jan 15, 2011·JACC. Cardiovascular Imaging·Marvin A KonstamJames E Udelson
May 4, 2011·The Journal of Clinical Investigation·Norimichi KoitabashiDavid A Kass
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Jan 5, 2012·Circulation·Véronique L RogerUNKNOWN American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Aug 17, 2012·The New England Journal of Medicine·Mark A DawsonBrian J P Huntly
Aug 21, 2012·Cell·Martin M MatzukJames E Bradner
Dec 22, 2012·Nature Reviews. Molecular Cell Biology·Marjorie MailletJeffery D Molkentin
Jan 3, 2013·The Journal of Clinical Investigation·Jop H van BerloJeffery D Molkentin
Mar 19, 2013·Cell·Tong Ihn Lee, Richard A Young
Jul 28, 2013·Circulation Research·Eugene Braunwald
Aug 14, 2013·Journal of Molecular and Cellular Cardiology·Jessica I SpiltoirTimothy A McKinsey
Oct 15, 2013·Cell·Denes HniszRichard A Young
Oct 17, 2013·Cardiovascular Research·Bernhard UnsöldGerd Hasenfuß
Dec 18, 2013·Bioinformatics·Andreas KrämerStuart Tugendreich
Jan 5, 2014·Cold Spring Harbor Perspectives in Medicine·Diane FatkinJonathan G Seidman
May 20, 2014·Journal of Molecular and Cellular Cardiology·Saptarsi M Haldar, Timothy A McKinsey
Jun 7, 2014·Molecular Cell·Junwei Shi, Christopher R Vakoc
Jul 30, 2014·Proceedings of the National Academy of Sciences of the United States of America·Scot J MatkovichGerald W Dorn
Sep 18, 2014·Circulation. Heart Failure·Thomas G Di Salvo, Saptarsi M Haldar
Sep 30, 2014·Molecular Cell·Jonathan D BrownJorge Plutzky
Mar 31, 2015·Circulation Research·Douglas L Mann

❮ Previous
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Citations

Sep 3, 2017·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jing Du, Yong Han
Mar 2, 2018·Journal of Leukocyte Biology·Guillaume P AndrieuGerald V Denis
May 26, 2018·Circulation Research·Manuel Rosa-GarridoThomas M Vondriska
Dec 3, 2017·The Journal of Cell Biology·David V HansenMorgan Sheng
Nov 2, 2017·The Journal of Experimental Medicine·Yu Matsuzawa-IshimotoKen Cadwell
Apr 12, 2019·Heart Failure Reviews·Rachel A MinerathChad E Grueter
Dec 7, 2018·Hematology·William Shomali, Jason Gotlib
Mar 31, 2019·The Journal of Physiology·Arun Padmanabhan, Saptarsi M Haldar
Jun 2, 2017·Nature Reviews. Cardiology·Dario Ummarino
May 24, 2019·Circulation Research·Miguel Pinilla-VeraDavid A Kass
May 31, 2019·Science·Casey A GiffordDeepak Srivastava
Dec 13, 2018·Current Drug Targets·Xiaotong WangYe Yuan
May 3, 2019·American Journal of Respiratory and Critical Care Medicine·Diederik E Van der FeenMarie-José Goumans
Nov 22, 2019·British Journal of Pharmacology·Prakash ChelladuraiSoni Savai Pullamsetti
Apr 24, 2020·Circulation Research·Patricia Cristine BorckJorge Plutzky
Feb 28, 2020·The Journal of Clinical Investigation·Austin HsuSaptarsi M Haldar
Jul 25, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jianle WangXiaolei Zhang
Mar 25, 2020·Current Opinion in Cardiology·Sadhan DasRama Natarajan
Apr 25, 2020·Physiological Reviews·Roberto PapaitGianluigi Condorelli
Sep 15, 2020·Medicinal Research Reviews·Ewelina KulikowskiNorman C W Wong
Jul 1, 2017·Nature Reviews. Drug Discovery·Megan Cully
Jul 13, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Mark E PepinOmar Wever-Pinzon
Jun 3, 2020·The Journal of Clinical Investigation·Gaelle AugusteAli J Marian
Aug 1, 2018·Cell Death Discovery·Mingli QuQingjun Zhou
Jul 6, 2019·Nature Reviews. Drug Discovery·Andrea G CochranRobert J Sims
Jul 20, 2017·F1000Research·Matthew S StrattonTimothy A McKinsey
Aug 15, 2019·Circulation Research·Matthew S StrattonTimothy A McKinsey
Jan 20, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Zhen XiaoYong Han
Nov 30, 2018·Molecular Medicine Reports·Qian WangYan Meng
Dec 20, 2018·Circulation Research·Michael Alexanian, Saptarsi M Haldar
Jan 30, 2019·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·C Mary Schooling, Jie V Zhao
Feb 23, 2020·Circulation Research·Haobo LiAnthony Rosenzweig

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