{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:54:01Z","timestamp":1790481241878,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Myocardial macrophages have key roles in cardiac remodeling and dysfunction. The gamma-aminobutyric acid subtype A (GABA<jats:sub>A<\/jats:sub>) receptor was recently found to be distributed in macrophages, allowing regulation of inflammatory responses to various diseases. This study aimed to clarify the role of GABA<jats:sub>A<\/jats:sub> receptor-mediated macrophage responses in pressure overload-induced heart failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>C57BL\/6J mice underwent transverse aortic constriction for pressure-overload hypertrophy (POH) and were intraperitoneally treated with a specific GABA<jats:sub>A<\/jats:sub> receptor agonist (topiramate) or antagonist (bicuculline). Echocardiography, histology, and flow cytometry were performed to evaluate the causes and effects of myocardial hypertrophy and fibrosis. Activation of the GABA<jats:sub>A<\/jats:sub> receptor by topiramate reduced ejection fraction and fractional shortening, enlarged the end-diastolic and end-systolic left ventricular internal diameter, aggravated myocardial hypertrophy and fibrosis, and accelerated heart failure in response to pressure overload. Mechanistically, topiramate increased the number of Ly6C<jats:sup>low<\/jats:sup> macrophages in the heart during POH and circulating Ly6C<jats:sup>high<\/jats:sup> classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6C<jats:sup>low<\/jats:sup> macrophages toward MHCII<jats:sup>high<\/jats:sup> macrophage polarization. As a result, Ly6C<jats:sup>low<\/jats:sup> macrophages activated the amphiregulin-induced AKT\/mTOR signaling pathway, and Ly6C<jats:sup>low<\/jats:sup>MHCII<jats:sup>high<\/jats:sup> macrophage polarization increased expression levels of osteopontin and TGF-\u03b2, which led to myocardial hypertrophy and fibrosis. Conversely, GABA<jats:sub>A<\/jats:sub> receptor blockage with bicuculline reversed these effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Control of the GABA<jats:sub>A<\/jats:sub> receptor activity in monocytes\/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABA<jats:sub>A<\/jats:sub> receptor has the potential to improve pressure overload-induced heart failure.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.670153","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T07:44:51Z","timestamp":1622447091000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["The GABAA Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Jin","family":"Bu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(14)61889-4","article-title":"The War Against Heart Failure: The Lancet Lecture","volume":"385","author":"Braunwald","year":"2015","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.013894","article-title":"Inhibition of Hypertrophy is a Good Therapeutic Strategy in Ventricular Pressure Overload","volume":"131","author":"Schiattarella","year":"2015","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1093\/eurjhf\/hft064","article-title":"The Epidemiology of Heart Failure, Based on Data for 2.1 Million Inhabitants in Sweden","volume":"15","author":"Zarrinkoub","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-019-01505-y","article-title":"Characteristics and Outcomes of HFpEF With Declining Ejection Fraction","volume":"109","author":"Park","year":"2020","journal-title":"Clin Res Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.187","article-title":"MicroRNA-221 Inhibits Autophagy and Promotes Heart Failure by Modulating the P27\/CDK2\/mTOR Axis","volume":"22","author":"Su","year":"2015","journal-title":"Cell Death Differ"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14680","article-title":"T Cell Costimulation Blockade Blunts Pressure Overload-Induced Heart Failure","volume":"8","author":"Kallikourdis","year":"2017","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.03.017","article-title":"Development and Function of Tissue Resident Macrophages in Mice","volume":"27","author":"Kierdorf","year":"2015","journal-title":"Semin Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.immuni.2013.11.019","article-title":"Embryonic and Adult-Derived Resident Cardiac Macrophages Are Maintained Through Distinct Mechanisms At Steady State and During Inflammation","volume":"40","author":"Epelman","year":"2014","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720065115","article-title":"Distinct Roles of Resident and Nonresident Macrophages in Nonischemic Cardiomyopathy","volume":"115","author":"Liao","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.018","article-title":"Tissue-Resident Macrophage Enhancer Landscapes are Shaped by the Local Microenvironment","volume":"159","author":"Lavin","year":"2014","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.001357","article-title":"Macrophage microRNA-155 Promotes Cardiac Hypertrophy and Failure","volume":"128","author":"Heymans","year":"2013","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.10.126","article-title":"Macrophages Dictate the Progression and Manifestation of Hypertensive Heart Disease","volume":"203","author":"Kain","year":"2016","journal-title":"Int J Cardiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0915139107","article-title":"Inhibitory Role for GABA in Autoimmune Inflammation","volume":"107","author":"Bhat","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx027","article-title":"Topiramate Modulates Post-Infarction Inflammation Primarily by Targeting Monocytes or Macrophages","volume":"113","author":"Wang","year":"2017","journal-title":"Cardiovasc Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1136\/gutjnl-2018-317479","article-title":"GABRP Regulates Chemokine Signalling, Macrophage Recruitment and Tumour Progression in Pancreatic Cancer Through Tuning KCNN4-Mediated Ca(2+) Signalling in a GABA-independent Manner","volume":"68","author":"Jiang","year":"2019","journal-title":"Gut"},{"key":"B16","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1053\/j.gastro.2018.05.033","article-title":"Gabaa Receptor Subtypes Regulate Stress-Induced Colon Inflammation in Mice","volume":"155","author":"Seifi","year":"2018","journal-title":"Gastroenterology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.18.8277","article-title":"Segregation of Atrial-Specific and Inducible Expression of an Atrial Natriuretic Factor Transgene in an In Vivo Murine Model of Cardiac Hypertrophy","volume":"88","author":"Rockman","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.117.09262","article-title":"P2y12 Receptor Promotes Pressure Overload-Induced Cardiac Remodeling Via Platelet-Driven Inflammation in Mice","volume":"70","author":"Wu","year":"2017","journal-title":"Hypertension"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.07.789","article-title":"Bone Marrow-Derived Tenascin-C Attenuates Cardiac Hypertrophy by Controlling Inflammation","volume":"70","author":"Song","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.ebiom.2018.08.022","article-title":"TRPA1 Inhibition Ameliorates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis in Mice","volume":"36","author":"Wang","year":"2018","journal-title":"EBio Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116581","article-title":"Colonic Electrical Stimulation Improves Colonic Transit in Rotenone-Induced Parkinson\u2019s Disease Model Through Affecting Enteric Neurons","volume":"231","author":"Bu","year":"2019","journal-title":"Life Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4326","article-title":"A Heart\u2013Brain\u2013Kidney Network Controls Adaptation to Cardiac Stress Through Tissue Macrophage Activation","volume":"23","author":"Fujiu","year":"2017","journal-title":"Nat Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/RES.0b013e3182582523","article-title":"Animal Models of Heart Failure: A Scientific Statement From the American Heart Association","volume":"111","author":"Houser","year":"2012","journal-title":"Circ Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8597-5_14","article-title":"Conventional Method of Transverse Aortic Constriction in Mice","volume":"1816","author":"Yoo","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"4184","DOI":"10.1038\/s41467-018-06487-5","article-title":"Gabaergic Signaling Linked to Autophagy Enhances Host Protection Against Intracellular Bacterial Infections","volume":"9","author":"Kim","year":"2018","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00132","article-title":"Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors","volume":"10","author":"Malaguarnera","year":"2019","journal-title":"Front Pharmacol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.jneuroim.2012.11.001","article-title":"Systemic Treatment With the Inhibitory Neurotransmitter Gamma-Aminobutyric Acid Aggravates Experimental Autoimmune Encephalomyelitis by Affecting Proinflammatory Immune Responses","volume":"255","author":"Carmans","year":"2013","journal-title":"J Neuroimmunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1406508111","article-title":"Distinct Macrophage Lineages Contribute to Disparate Patterns of Cardiac Recovery and Remodeling in the Neonatal and Adult Heart","volume":"111","author":"Lavine","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40096","article-title":"Excessive Cardiac Insulin Signaling Exacerbates Systolic Dysfunction Induced by Pressure Overload in Rodents","volume":"120","author":"Shimizu","year":"2010","journal-title":"J Clin Invest"},{"key":"B30","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1161\/CIRCRESAHA.117.311147","article-title":"New Insights Into the Role of Mtor Signaling in the Cardiovascular System","volume":"122","author":"Sciarretta","year":"2018","journal-title":"Circ Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171274","article-title":"Cardiac Macrophages Promote Diastolic Dysfunction","volume":"215","author":"Hulsmans","year":"2018","journal-title":"J Exp Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.6MR0118-041R","article-title":"Specialized Functions of Resident Macrophages in Brain and Heart","volume":"104","author":"Nicolas-Avila","year":"2018","journal-title":"J Leukoc Biol"}],"updated-by":[{"DOI":"10.3389\/fimmu.2021.753404","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.670153\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T11:25:06Z","timestamp":1632223506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.670153\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,31]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2021.670153"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.670153","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fimmu.2021.753404","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,31]]},"article-number":"670153"}}