{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:34Z","timestamp":1791312694795,"version":"4.3.1"},"reference-count":112,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T00:00:00Z","timestamp":1625270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RA2717\/2\u20101"],"award-info":[{"award-number":["RA2717\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.<\/jats:p>","DOI":"10.3390\/cells10071681","type":"journal-article","created":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T22:34:36Z","timestamp":1625438076000},"page":"1681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["RhoA Signaling in Immune Cell Response and Cardiac Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Lucia Sophie","family":"Kilian","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany"},{"name":"DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derk","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany"},{"name":"DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2630-9754","authenticated-orcid":false,"given":"Ashraf Yusuf","family":"Rangrez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany"},{"name":"DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"},{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/CIRCRESAHA.116.308030","article-title":"Chronic Heart Failure and Inflammation: What Do We Really Know?","volume":"119","author":"Dick","year":"2016","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1056\/NEJM199007263230405","article-title":"Elevated circulating levels of tumor necrosis factor in severe chronic heart failure","volume":"323","author":"Levine","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/CIRCRESAHA.116.302317","article-title":"Innate immunity and the failing heart: The cytokine hypothesis revisited","volume":"116","author":"Mann","year":"2015","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/ejhf.430","article-title":"Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: Critical appraisal and practical use","volume":"17","author":"Vaduganathan","year":"2015","journal-title":"Eur. J. Heart Fail."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1172\/JCI118095","article-title":"Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes","volume":"96","author":"Thaik","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1161\/01.CIR.95.5.1247","article-title":"Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes","volume":"95","author":"Yokoyama","year":"1997","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6668","DOI":"10.1073\/pnas.111155798","article-title":"Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes","volume":"98","author":"Purcell","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jacbts.2017.12.006","article-title":"CCR2(+) Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload","volume":"3","author":"Patel","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Weisheit, C., Zhang, Y., Faron, A., Kopke, O., Weisheit, G., Steinstrasser, A., Frede, S., Meyer, R., Boehm, O., and Hoeft, A. (2014). Ly6C(low) and not Ly6C(high) macrophages accumulate first in the heart in a model of murine pressure-overload. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112710"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E4661","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":"ref_11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/cvr\/cvs142","article-title":"A pro-fibrotic role for interleukin-4 in cardiac pressure overload","volume":"95","author":"Kanellakis","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/ejhf.1138","article-title":"The innate immune system in chronic cardiomyopathy: A European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC","volume":"20","author":"Frantz","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bros, M., Haas, K., Moll, L., and Grabbe, S. (2019). RhoA as a Key Regulator of Innate and Adaptive Immunity. Cells, 8.","DOI":"10.3390\/cells8070733"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5773","DOI":"10.1091\/mbc.e05-04-0358","article-title":"Plasma membrane organization is essential for balancing competing pseudopod- and uropod-promoting signals during neutrophil polarization and migration","volume":"16","author":"Bodin","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12929-021-00730-w","article-title":"RhoA: A dubious molecule in cardiac pathophysiology","volume":"28","author":"Kilian","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/cvr\/cvu025","article-title":"Cardiac macrophages and their role in ischaemic heart disease","volume":"102","author":"Frantz","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1248\/bpb.28.886","article-title":"Tissue-specific mRNA expression profiles of human toll-like receptors and related genes","volume":"28","author":"Nishimura","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1177\/039463200902200208","article-title":"Inflammasomes are differentially expressed in cardiovascular and other tissues","volume":"22","author":"Yin","year":"2009","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2014.01.062","article-title":"Innate immunity and cardiomyocytes in ischemic heart disease","volume":"100","author":"Lin","year":"2014","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.immuni.2011.05.006","article-title":"Toll-like receptors and their crosstalk with other innate receptors in infection and immunity","volume":"34","author":"Kawai","year":"2011","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1074\/jbc.M115.689620","article-title":"Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase\/Serum-response Factor and beta-Catenin\/GSK-3beta Protein Signaling","volume":"291","author":"Rangrez","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.peptides.2014.06.011","article-title":"Atrial natriuretic peptide: An old hormone or a new cytokine?","volume":"58","year":"2014","journal-title":"Peptides"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.healun.2004.06.023","article-title":"Neuroendocrine profiling of humans receiving cardiac allografts","volume":"24","author":"Ogawa","year":"2005","journal-title":"J. Heart Lung Transplant."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1161\/01.RES.0000017068.58856.F3","article-title":"Inhibition of p38 MAPK activation via induction of MKP-1: Atrial natriuretic peptide reduces TNF-alpha-induced actin polymerization and endothelial permeability","volume":"90","author":"Kiemer","year":"2002","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1161\/01.ATV.0000037102.31086.F4","article-title":"Pharmacological potentiation of natriuretic peptide limits polymorphonuclear neutrophil-vascular cell interactions","volume":"22","author":"Houard","year":"2002","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1161\/CIRCRESAHA.115.307196","article-title":"Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction","volume":"119","author":"Chen","year":"2016","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12967-017-1189-5","article-title":"Analysis of necroptotic proteins in failing human hearts","volume":"15","author":"Szobi","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.12659\/MSMBR.913436","article-title":"Autophagy and Oncosis\/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients","volume":"25","author":"Corsetti","year":"2019","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s10517-013-2124-2","article-title":"Study of cardioprotective effects of necroptosis inhibitors on isolated rat heart subjected to global ischemia-reperfusion","volume":"155","author":"Dmitriev","year":"2013","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00540-013-1716-3","article-title":"Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury","volume":"28","author":"Koshinuma","year":"2014","journal-title":"J. Anesth."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1161\/ATVBAHA.111.224915","article-title":"Mechanisms of cell death in heart disease","volume":"32","author":"Konstantinidis","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s11596-019-2067-6","article-title":"Implications of Necroptosis for Cardiovascular Diseases","volume":"39","author":"Ruan","year":"2019","journal-title":"Curr. Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Miao, K., Zhou, L., Ba, H., Li, C., Gu, H., Yin, B., Wang, J., Yang, X.P., Li, Z., and Wang, D.W. (2020). Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000967"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1007\/s11033-021-06289-x","article-title":"Necroptosis and RhoA\/ROCK pathways: Molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia\/reperfusion injury in a rat model","volume":"48","author":"Sharifi","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.yjmcc.2015.11.015","article-title":"Monocyte and macrophage contributions to cardiac remodeling","volume":"93","author":"Hulsmans","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00395-020-00836-6","article-title":"Resident cardiac macrophages: Crucial modulators of cardiac (patho)physiology","volume":"115","author":"Sansonetti","year":"2020","journal-title":"Basic Res. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.yexcr.2016.02.004","article-title":"Mouse macrophage polarity and ROCK1 activity depend on RhoA and non-apoptotic Caspase 3","volume":"341","author":"Liu","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.jacc.2015.07.023","article-title":"Prognostic Relevance of Gene-Environment Interactions in Patients with Dilated Cardiomyopathy: Applying the MOGE(S) Classification","volume":"66","author":"Hazebroek","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.yjmcc.2016.12.002","article-title":"Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation","volume":"102","author":"Lynch","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1586\/14779072.2015.990385","article-title":"Immunoadsorption therapy in dilated cardiomyopathy","volume":"13","author":"Felix","year":"2015","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.cardfail.2014.11.004","article-title":"Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: Evidence of M2 macrophage activation in disease pathogenesis","volume":"21","author":"Glezeva","year":"2015","journal-title":"J. Card. Fail."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1161\/CIRCULATIONAHA.112.112185","article-title":"Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-kappaB","volume":"126","author":"Verma","year":"2012","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1161\/CIRCULATIONAHA.112.097832","article-title":"Immune cell modulation of cardiac remodeling","volume":"125","author":"Mortensen","year":"2012","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1161\/CIRCULATIONAHA.111.052126","article-title":"Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling","volume":"125","author":"Anzai","year":"2012","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1161\/CIRCULATIONAHA.113.007101","article-title":"CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload","volume":"129","author":"Laroumanie","year":"2014","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1161\/CIRCHEARTFAILURE.115.002225","article-title":"Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure","volume":"8","author":"Nevers","year":"2015","journal-title":"Circulation Heart Fail."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/21541248.2017.1332505","article-title":"Go with the flow: GEF-H1 mediated shear stress mechanotransduction in neutrophils","volume":"11","author":"Fine","year":"2020","journal-title":"Small GTPases"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14680","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":"ref_51","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.devcel.2016.06.031","article-title":"Leading from the Back: The Role of the Uropod in Neutrophil Polarization and Migration","volume":"38","author":"Hind","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.cellbio.21.020604.150721","article-title":"Rho GTPases: Biochemistry and biology","volume":"21","author":"Jaffe","year":"2005","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.cell.2007.05.018","article-title":"GEFs and GAPs: Critical elements in the control of small G proteins","volume":"129","author":"Bos","year":"2007","journal-title":"Cell"},{"key":"ref_54","first-page":"1321","article-title":"Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins","volume":"5","author":"Fukumoto","year":"1990","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.4049\/jimmunol.0803838","article-title":"The mDial formin is required for neutrophil polarization, migration, and activation of the LARG\/RhoA\/ROCK signaling axis during chemotaxis","volume":"182","author":"Shi","year":"2009","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.imbio.2018.07.009","article-title":"Inhibition of RhoA and mTORC2\/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages","volume":"223","author":"Chen","year":"2018","journal-title":"Immunobiology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1182\/blood-2005-03-1164","article-title":"Rho GEF Lsc is required for normal polarization, migration, and adhesion of formyl-peptide-stimulated neutrophils","volume":"107","author":"Francis","year":"2006","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s12265-010-9192-8","article-title":"Revisited and revised: Is RhoA always a villain in cardiac pathophysiology?","volume":"3","author":"Miyamoto","year":"2010","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"H2802","DOI":"10.1152\/ajpheart.01162.2004","article-title":"Lysophosphatidic acid-mediated augmentation of cardiomyocyte lipoprotein lipase involves actin cytoskeleton reorganization","volume":"288","author":"Pulinilkunnil","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1476-5381.2009.00121.x","article-title":"Regulation of RhoGEF proteins by G12\/13-coupled receptors","volume":"158","author":"Siehler","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"18925","DOI":"10.1074\/jbc.M112.352260","article-title":"Acute activation of beta2-adrenergic receptor regulates focal adhesions through betaArrestin2- and p115RhoGEF protein-mediated activation of RhoA","volume":"287","author":"Ma","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1091\/mbc.e02-12-0781","article-title":"The GTP-binding protein RhoA mediates Na,K-ATPase exocytosis in alveolar epithelial cells","volume":"14","author":"Lecuona","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/j.jacc.2009.05.015","article-title":"The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications","volume":"54","author":"Triposkiadis","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"904","DOI":"10.3389\/fphar.2018.00904","article-title":"New Insights in Cardiac beta-Adrenergic Signaling During Heart Failure and Aging","volume":"9","author":"Eguchi","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJM198409273111303","article-title":"Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure","volume":"311","author":"Cohn","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1536\/ihj.17-313","article-title":"Catecholamine-Induced Senescence of Endothelial Cells and Bone Marrow Cells Promotes Cardiac Dysfunction in Mice","volume":"59","author":"Katsuumi","year":"2018","journal-title":"Int. Heart J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1179\/135100002125000389","article-title":"Catecholamine effects on cardiac remodelling, oxidative stress and fibrosis in experimental heart failure","volume":"7","author":"Mahmoudi","year":"2002","journal-title":"Redox Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1161\/CIRCRESAHA.117.310520","article-title":"Adrenergic Receptors in Individual Ventricular Myocytes: The Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent","volume":"120","author":"Myagmar","year":"2017","journal-title":"Circ. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1242\/jcs.02314","article-title":"BCL6 suppresses RhoA activity to alter macrophage morphology and motility","volume":"118","author":"Pixley","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"12145","DOI":"10.1073\/pnas.0911986107","article-title":"Motorized RhoGAP myosin IXb (Myo9b) controls cell shape and motility","volume":"107","author":"Hanley","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"21271","DOI":"10.1074\/jbc.M116.738617","article-title":"Kruppel-like Factor 6 Promotes Macrophage-mediated Inflammation by Suppressing B Cell Leukemia\/Lymphoma 6 Expression","volume":"291","author":"Kim","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"23371","DOI":"10.1074\/jbc.272.37.23371","article-title":"Direct interaction of the Rho GDP dissociation inhibitor with ezrin\/radixin\/moesin initiates the activation of the Rho small G protein","volume":"272","author":"Takahashi","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.3389\/fimmu.2018.01407","article-title":"Transforming Growth Factor-beta1\/Smad7 in Intestinal Immunity, Inflammation, and Cancer","volume":"9","author":"Troncone","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1182\/blood-2005-10-009191","article-title":"Transforming growth factor-beta1 regulates macrophage migration via RhoA","volume":"108","author":"Kim","year":"2006","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/ncb3284","article-title":"Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells","volume":"18","author":"Vargas","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"28599","DOI":"10.1074\/jbc.M109.047282","article-title":"Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5","volume":"284","author":"Wang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.4049\/jimmunol.1300695","article-title":"Dendritic cell motility and T cell activation requires regulation of Rho-cofilin signaling by the Rho-GTPase activating protein myosin IXb","volume":"192","author":"Xu","year":"2014","journal-title":"J. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1182\/blood-2012-03-417923","article-title":"Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation","volume":"120","author":"Nitschke","year":"2012","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"28687","DOI":"10.1074\/jbc.M113.461277","article-title":"The switch-associated protein 70 (SWAP-70) bundles actin filaments and contributes to the regulation of F-actin dynamics","volume":"288","author":"Kiessling","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10059-012-0055-9","article-title":"Over-expression of a RhoA-specific guanine nucleotide exchange factor, p190RhoGEF, in mouse dendritic cells negatively regulates cellular responses to bacterial lipopolysaccharide","volume":"34","author":"Seul","year":"2012","journal-title":"Mol. Cells"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1083\/jcb.200103048","article-title":"RhoA is required for monocyte tail retraction during transendothelial migration","volume":"154","author":"Worthylake","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.bpj.2011.05.040","article-title":"Traction Forces of Neutrophils Migrating on Compliant Substrates","volume":"101","author":"Jannat","year":"2011","journal-title":"Biophys J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1083\/jcb.200706167","article-title":"PDZRhoGEF and myosin II localize RhoA activity to the back of polarizing neutrophil-like cells","volume":"179","author":"Wong","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_84","first-page":"35","article-title":"Positive feedback between Dia1, larg and Rhoa is required for cancer cell invasion","volume":"375","author":"Kitzing","year":"2007","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0092-8674(03)00555-5","article-title":"Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils","volume":"114","author":"Xu","year":"2003","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1073\/pnas.0600092103","article-title":"Neutrophil polarization: Spatiotemporal dynamics of RhoA activity support a self-organizing mechanism","volume":"103","author":"Wong","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/ncb3292","article-title":"Locally excitable Cdc42 signals steer cells during chemotaxis","volume":"18","author":"Yang","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ricker, E., Chowdhury, L., Yi, W., and Pernis, A.B. (2016). The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Research, 5.","DOI":"10.12688\/f1000research.7522.1"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.bcp.2014.10.002","article-title":"Combretastatin (CA)-4 and its novel analogue CA-432 impair T-cell migration through the Rho\/ROCK signalling pathway","volume":"92","author":"Pollock","year":"2014","journal-title":"Biochem. Pharm."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1084\/jem.20170896","article-title":"The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8(+) T cells","volume":"215","author":"Moalli","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"350","DOI":"10.4049\/jimmunol.175.1.350","article-title":"Integrin regulation by RhoA in thymocytes","volume":"175","author":"Vielkind","year":"2005","journal-title":"J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1182\/blood-2008-04-152587","article-title":"SWAP-70 regulates RhoA\/RhoB-dependent MHCII surface localization in dendritic cells","volume":"113","author":"Wahren","year":"2009","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.4049\/jimmunol.1203095","article-title":"SWAP-70 restricts spontaneous maturation of dendritic cells","volume":"190","author":"Gotz","year":"2013","journal-title":"J. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5973","DOI":"10.4049\/jimmunol.1400839","article-title":"Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development","volume":"193","author":"Zhang","year":"2014","journal-title":"J. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1385\/IR:32:1-3:259","article-title":"The Vav family: At the crossroads of signaling pathways","volume":"32","author":"Swat","year":"2005","journal-title":"Immunol. Res."},{"key":"ref_96","first-page":"ra49","article-title":"The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway","volume":"8","author":"Goodfellow","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1189\/jlb.0206120","article-title":"Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells","volume":"82","author":"Helms","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.molcel.2004.12.012","article-title":"RhoA GTPase regulates B cell receptor signaling","volume":"17","author":"Saci","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4049\/jimmunol.170.1.19","article-title":"Induced expression of a RhoA-specifiic guanine nucleotide exchange factor, p190RhoGEF, following CD40 stimulation and WEHI 231 B cell activation","volume":"170","author":"Lee","year":"2003","journal-title":"J. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Saha, S., Nagy, T.L., and Weiner, O.D. (2018). Joining forces: Crosstalk between biochemical signalling and physical forces orchestrates cellular polarity and dynamics. Philos. Trans. R. Soc. Lond. B Biol. Sci., 373.","DOI":"10.1098\/rstb.2017.0145"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1091\/mbc.E19-04-0207","article-title":"Cellular self-organization: Generating order from the abyss","volume":"31","author":"McCusker","year":"2020","journal-title":"Mol. Biol. Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/21541248.2016.1224399","article-title":"Rac1 and RhoA: Networks, loops and bistability","volume":"9","author":"Nguyen","year":"2018","journal-title":"Small GTPases"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ccell.2018.01.001","article-title":"RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis","volume":"33","author":"Cortes","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/leu.2017.273","article-title":"Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma","volume":"32","author":"Fujisawa","year":"2018","journal-title":"Leukemia"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Leong, D., Aghel, N., Hillis, C., Siegal, D., Karampatos, S., Rangarajan, S., Pond, G., and Seow, H. (2021). Tyrosine kinase inhibitors in chronic myeloid leukaemia and emergent cardiovascular disease. Heart.","DOI":"10.1136\/heartjnl-2020-318251"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1515\/hsz-2013-0181","article-title":"Rho-kinase: Regulation, (dys)function, and inhibition","volume":"394","author":"Amin","year":"2013","journal-title":"Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1111\/j.1600-6143.2009.02831.x","article-title":"TNF receptors differentially signal and are differentially expressed and regulated in the human heart","volume":"9","author":"Brookes","year":"2009","journal-title":"Am. J. Transplant."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"35564","DOI":"10.1074\/jbc.M704003200","article-title":"TNFR1 and TNFR2 signaling interplay in cardiac myocytes","volume":"282","author":"Defer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3389\/fcell.2019.00091","article-title":"TNFR1 and TNFR2 in the Control of the Life and Death Balance of Macrophages","volume":"7","author":"Wajant","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1161\/01.CIR.98.12.1184","article-title":"Clinical effects of beta-adrenergic blockade in chronic heart failure: A meta-analysis of double-blind, placebo-controlled, randomized trials","volume":"98","author":"Lechat","year":"1998","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1056\/NEJM199608153350707","article-title":"The management of chronic heart failure","volume":"335","author":"Cohn","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ppedcard.2010.11.007","article-title":"The Role of Beta-Adrenergic Receptors in Heart Failure: Differential Regulation of Cardiotoxicity and Cardioprotection","volume":"31","author":"Bernstein","year":"2011","journal-title":"Prog. Pediatr. Cardiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1681\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:32Z","timestamp":1760163932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,3]]},"references-count":112,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cells10071681"],"URL":"https:\/\/doi.org\/10.3390\/cells10071681","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,3]]}}}