{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:08:27Z","timestamp":1789999707321,"version":"4.0.1"},"reference-count":97,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17SDG33400114"],"award-info":[{"award-number":["17SDG33400114"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibroblasts are an important resident cell population in the heart involved in maintaining homeostasis and structure during normal conditions. They are also crucial in disease states for sensing signals and initiating the appropriate repair responses to maintain the structural integrity of the heart. This sentinel role of cardiac fibroblasts occurs, in part, through their ability to secrete cytokines. \u03b2-adrenergic receptors (\u03b2AR) are also critical regulators of cardiac function in the normal and diseased state and a major therapeutic target clinically. \u03b2AR are known to influence cytokine secretion in various cell types and they have been shown to be involved in cytokine production in the heart, but their role in regulating cytokine production in cardiac fibroblasts is not well understood. Thus, we hypothesized that \u03b2AR activation on cardiac fibroblasts modulates cytokine production to influence fibroblast function. Using primary fibroblast cultures from neonatal rats and adult mice, increased interleukin (IL)-6 expression and secretion occurred following \u03b22AR activation. The use of pharmacological inhibitors and genetic manipulations showed that IL-6 elevations occurred through the G\u03b1s-mediated activation of ERK1\/2 and resulted in increased fibroblast proliferation. In vivo, a lack of \u03b22AR resulted in increased infarct size following myocardial infarction and impaired wound closure in a murine dermal wound healing assay. These findings identify an important role for \u03b22AR in regulating fibroblast proliferation through G\u03b1s\/ERK1\/2-dependent alterations in IL-6 and may lead to the development of improved heart failure therapies through targeting fibrotic function of \u03b22AR.<\/jats:p>","DOI":"10.3390\/ijms21228507","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T10:00:32Z","timestamp":1605175232000},"page":"8507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["\u03b22-Adrenergic Receptors Increase Cardiac Fibroblast Proliferation Through the G\u03b1s\/ERK1\/2-Dependent Secretion of Interleukin-6"],"prefix":"10.3390","volume":"21","author":[{"given":"Miles A.","family":"Tanner","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toby P.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2075-3926","authenticated-orcid":false,"given":"Charles A.","family":"Maitz","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel A.","family":"Grisanti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/CIRCRESAHA.109.209809","article-title":"Cardiac fibroblast: The renaissance cell","volume":"105","author":"Souders","year":"2009","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1093\/cvr\/cvq329","article-title":"Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation","volume":"89","author":"Yue","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.yjmcc.2016.03.005","article-title":"Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems","volume":"94","author":"Pellman","year":"2016","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1042\/BST20150035","article-title":"Electrical consequences of cardiac myocyte: Fibroblast coupling","volume":"43","author":"McArthur","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1161\/CIRCRESAHA.107.149047","article-title":"Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling","volume":"101","author":"Oka","year":"2007","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e001993","DOI":"10.1161\/JAHA.115.001993","article-title":"Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo","volume":"4","author":"Zhang","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1196\/annals.1380.007","article-title":"Dynamic interactions between myocytes, fibroblasts, and extracellular matrix","volume":"1080","author":"Banerjee","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1172\/JCI74783","article-title":"Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis","volume":"124","author":"Banerjee","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.yjmcc.2017.11.012","article-title":"Resident fibroblast expansion during cardiac growth and remodeling","volume":"114","author":"Ivey","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.devcel.2008.12.007","article-title":"Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling","volume":"16","author":"Ieda","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI94753","article-title":"Fibroblast-specific TGF-beta-Smad2\/3 signaling underlies cardiac fibrosis","volume":"127","author":"Khalil","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jbiomech.2009.09.020","article-title":"The myofibroblast: Paradigm for a mechanically active cell","volume":"43","author":"Hinz","year":"2010","journal-title":"J. Biomech."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1172\/JCI83822","article-title":"Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction","volume":"127","author":"Nakaya","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e010013","DOI":"10.1161\/JAHA.118.010013","article-title":"Cardiac Fibrosis in Proteotoxic Cardiac Disease is Dependent Upon Myofibroblast TGF -beta Signaling","volume":"7","author":"Bhandary","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.smim.2014.01.003","article-title":"Neuroendocrine regulation of inflammation","volume":"26","author":"Padro","year":"2014","journal-title":"Semin Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.bbi.2015.08.012","article-title":"Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease","volume":"50","author":"Hong","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bbi.2018.09.004","article-title":"The beta2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion","volume":"74","author":"Agac","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.bbi.2014.10.007","article-title":"beta2-Adrenergic receptors in immunity and inflammation: Stressing NF-kappaB","volume":"45","author":"Kolmus","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15126","DOI":"10.1073\/pnas.1611023114","article-title":"beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury","volume":"113","author":"Grisanti","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/eurheartj\/ehx261","article-title":"IL-18 cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult","volume":"39","author":"Xiao","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pharmthera.2009.05.002","article-title":"Cardiac fibroblasts: At the heart of myocardial remodeling","volume":"123","author":"Porter","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/labinvest.2016.65","article-title":"Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-beta1 signaling pathway","volume":"96","author":"Wang","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.cyto.2018.09.021","article-title":"Human cardiac fibroblasts isolated from patients with severe heart failure are immune-competent cells mediating an inflammatory response","volume":"113","author":"Sandstedt","year":"2019","journal-title":"Cytokine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1067-1927.2005.130408.x","article-title":"Beta 2-adrenergic receptor activation delays dermal fibroblast-mediated contraction of collagen gels via a cAMP-dependent mechanism","volume":"13","author":"Pullar","year":"2005","journal-title":"Wound Repair Regen."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"34012","DOI":"10.1038\/srep34012","article-title":"Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis","volume":"6","author":"Uehara","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.yjmcc.2005.12.005","article-title":"Noncanonical cAMP pathway and p38 MAPK mediate beta2-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts","volume":"40","author":"Yin","year":"2006","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32430","DOI":"10.1038\/srep32430","article-title":"Proliferation in cardiac fibroblasts induced by beta1-adrenoceptor autoantibody and the underlying mechanisms","volume":"6","author":"Lv","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/S0008-6363(02)00729-0","article-title":"Chronic beta2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism","volume":"57","author":"Turner","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1111\/j.1365-2133.2007.07867.x","article-title":"Interleukin-6 (IL-6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL-6KO mice","volume":"156","author":"Luckett","year":"2007","journal-title":"Br. J. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/sj.jid.5700109","article-title":"IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice","volume":"126","author":"Gallucci","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ma, F., Li, Y., Han, Y., Cheng, J., Li, H., Qi, Y., and Du, J. (2012). Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF \u03b2\/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035144"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1158\/0008-5472.CAN-17-2268","article-title":"IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment","volume":"78","author":"Karakasheva","year":"2018","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/jlb.58.2.209","article-title":"Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation","volume":"58","author":"Yellin","year":"1995","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1161\/01.RES.85.11.1092","article-title":"Recent advances in cardiac beta(2)-adrenergic signal transduction","volume":"85","author":"Xiao","year":"1999","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"32116","DOI":"10.1074\/jbc.M204895200","article-title":"Beta-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases","volume":"277","author":"Kim","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1074\/jbc.M506576200","article-title":"beta-arrestin-dependent, G protein-independent ERK1\/2 activation by the beta2 adrenergic receptor","volume":"281","author":"Shenoy","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.cellsig.2004.05.002","article-title":"PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs\/Gi switching","volume":"16","author":"Martin","year":"2004","journal-title":"Cell. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1161\/CIRCULATIONAHA.116.022304","article-title":"Leukocyte-Expressed beta2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury","volume":"134","author":"Grisanti","year":"2016","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.devcel.2012.08.017","article-title":"A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo","volume":"23","author":"Davis","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1136\/bmj.39185.440382.47","article-title":"Beta blockers in hypertension and cardiovascular disease","volume":"334","author":"Ong","year":"2007","journal-title":"BMJ"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s10741-019-09825-x","article-title":"Beta-Adrenergic receptor, an essential target in cardiovascular diseases","volume":"25","author":"Ali","year":"2020","journal-title":"Heart Fail. Rev."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"7059","DOI":"10.1073\/pnas.96.12.7059","article-title":"Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice","volume":"96","author":"Engelhardt","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1172\/JCI200316326","article-title":"Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+\/calmodulin kinase II","volume":"111","author":"Zhu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.bbadis.2010.07.003","article-title":"Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation","volume":"1812","author":"Canales","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1016\/0024-3205(90)90276-W","article-title":"Characterization of beta adrenoceptors on cultured endothelial cells by radioligand binding","volume":"47","author":"Ahmad","year":"1990","journal-title":"Life Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.molimm.2009.12.013","article-title":"Pro-inflammatory responses in human monocytes are beta1-adrenergic receptor subtype dependent","volume":"47","author":"Grisanti","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"PMC7522448","DOI":"10.3389\/fphys.2020.529075","article-title":"The Dynamic Interplay Between Cardiac Inflammation and Fibrosis","volume":"11","author":"Thomas","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H316","DOI":"10.1152\/ajpheart.00635.2014","article-title":"Temporal and gefitinib-sensitive regulation of cardiac cytokine expression via chronic beta-adrenergic receptor stimulation","volume":"308","author":"Grisanti","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1161\/01.CIR.101.20.2338","article-title":"Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression","volume":"101","author":"Murray","year":"2000","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3109\/10799899909036645","article-title":"Participation of beta-adrenergic receptors on macrophages in modulation of LPS-induced cytokine release","volume":"19","author":"Izeboud","year":"1999","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.cellsig.2006.06.007","article-title":"Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms","volume":"19","author":"Tan","year":"2007","journal-title":"Cell. Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1111\/j.1476-5381.2011.01785.x","article-title":"beta-Adrenergic receptors stimulate interleukin-6 production through Epac-dependent activation of PKCdelta\/p38 MAPK signalling in neonatal mouse cardiac fibroblasts","volume":"166","author":"Chen","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"H14","DOI":"10.1152\/ajpheart.2001.281.1.H14","article-title":"Catecholamines stimulate interleukin-6 synthesis in rat cardiac fibroblasts","volume":"281","author":"Burger","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1742-2094-11-21","article-title":"Beta(2)-adrenergic agonists modulate TNF-alpha induced astrocytic inflammatory gene expression and brain inflammatory cell populations","volume":"11","author":"Laureys","year":"2014","journal-title":"J. Neuroinflammation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1023\/A:1011401825680","article-title":"The role of interleukin-6 in the failing heart","volume":"6","author":"Wollert","year":"2001","journal-title":"Heart Fail. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1242\/jcs.02772","article-title":"The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms","volume":"119","author":"Pullar","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/00075198-200210000-00005","article-title":"Positive inotropic stimulation","volume":"8","author":"Leone","year":"2002","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/FJC.0000000000000462","article-title":"Cardiac GPCR-Mediated EGFR Transactivation: Impact and Therapeutic Implications","volume":"70","author":"Grisanti","year":"2017","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4664","DOI":"10.7150\/thno.26619","article-title":"Pepducin-mediated cardioprotection via beta-arrestin-biased beta2-adrenergic receptor-specific signaling","volume":"8","author":"Grisanti","year":"2018","journal-title":"Theranostics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e00024","DOI":"10.1002\/prp2.24","article-title":"Dynamic mass redistribution analysis of endogenous beta-adrenergic receptor signaling in neonatal rat cardiac fibroblasts","volume":"2","author":"Carter","year":"2014","journal-title":"Pharmacol.Res. Perspect."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1073\/pnas.262787199","article-title":"beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi","volume":"100","author":"Baillie","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/36362","article-title":"Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A","volume":"390","author":"Daaka","year":"1997","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0008-6363(00)00170-X","article-title":"Comitogenic effect of catecholamines on rat cardiac fibroblasts in culture","volume":"48","author":"Leicht","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S0962-8924(02)02294-8","article-title":"Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation","volume":"12","author":"Stork","year":"2002","journal-title":"Trends Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1128\/MCB.21.11.3671-3683.2001","article-title":"Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1","volume":"21","author":"Schmitt","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.4049\/jimmunol.147.5.1628","article-title":"Rap1A is a substrate for cyclic AMP-dependent protein kinase in human neutrophils","volume":"147","author":"Quilliam","year":"1991","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1073\/pnas.082122499","article-title":"On the mitogenic properties of Rap1b: cAMP-induced G(1)\/S entry requires activated and phosphorylated Rap1b","volume":"99","author":"Urbani","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S1097-2765(01)00432-4","article-title":"PKA phosphorylation of Src mediates cAMP\u2019s inhibition of cell growth via Rap1","volume":"9","author":"Schmitt","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1006\/bbrc.1999.1919","article-title":"Activation of the small G protein Rap1 in dog thyroid cells by both cAMP-dependent and -independent pathways","volume":"267","author":"Dremier","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"18598","DOI":"10.1074\/jbc.M201868200","article-title":"Protein kinase A-independent activation of ERK and H,K-ATPase by cAMP in native kidney cells: Role of Epac I","volume":"277","author":"Marsy","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1161\/HYPERTENSIONAHA.109.148635","article-title":"Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats","volume":"56","author":"Melendez","year":"2010","journal-title":"Hypertension"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"12350","DOI":"10.1038\/s41598-020-69413-0","article-title":"Beneficial effects of IL-4 and IL-6 on rat neonatal target cardiac cells","volume":"10","author":"Zogbi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cyto.2014.12.024","article-title":"The varying faces of IL-6: From cardiac protection to cardiac failure","volume":"74","author":"Fontes","year":"2015","journal-title":"Cytokine"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/jcp.20307","article-title":"Role of interleukin-6 in cardiomyocyte\/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation","volume":"204","author":"Fredj","year":"2005","journal-title":"J. Cell. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.4161\/cc.8.8.8147","article-title":"How ERK1\/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?","volume":"8","author":"Mebratu","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ceb.2016.01.007","article-title":"The dynamic subcellular localization of ERK: Mechanisms of translocation and role in various organelles","volume":"39","author":"Wainstein","year":"2016","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.cellsig.2006.09.001","article-title":"The duration of ERK1\/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1","volume":"19","author":"Chalmers","year":"2007","journal-title":"Cell. Signal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1177\/1947601911407328","article-title":"The ERK Cascade: Distinct Functions within Various Subcellular Organelles","volume":"2","author":"Wortzel","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"721608","DOI":"10.1155\/2011\/721608","article-title":"The many faces of interleukin-6: The role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis","volume":"2011","author":"Barnes","year":"2011","journal-title":"Int. J. Rheumatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/ar1916","article-title":"Interleukin-6: Discovery of a pleiotropic cytokine","volume":"8","author":"Kishimoto","year":"2006","journal-title":"Arthritis Res. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/CIRCRESAHA.115.306565","article-title":"Cardiac Fibrosis: The Fibroblast Awakens","volume":"118","author":"Travers","year":"2016","journal-title":"Circ. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.2353\/ajpath.2007.070003","article-title":"Fibroblast growth factor-2 regulates myocardial infarct repair: Effects on cell proliferation, scar contraction, and ventricular function","volume":"171","author":"Virag","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1161\/01.RES.87.12.1172","article-title":"The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3\u2019-kinase","volume":"87","author":"Chesley","year":"2000","journal-title":"Circ. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1152\/japplphysiol.00106.2017","article-title":"Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans","volume":"123","author":"Maman","year":"2017","journal-title":"J. Appl. Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41536-018-0059-y","article-title":"Parallels between vertebrate cardiac and cutaneous wound healing and regeneration","volume":"3","author":"Richardson","year":"2018","journal-title":"NPJ Regen. Med."},{"key":"ref_88","first-page":"127","article-title":"Changes of immunoregulatory cells induced by psychological and physical stress: Relationship to plasma catecholamines","volume":"58","author":"Landmann","year":"1984","journal-title":"Clin. Exp. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.amjhyper.2004.07.007","article-title":"Beta-blocker improves survival, left ventricular function, and myocardial remodeling in hypertensive rats with diastolic heart failure","volume":"17","author":"Kobayashi","year":"2004","journal-title":"Am. J. Hypertens"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1093\/cvr\/cvp168","article-title":"Therapeutic effect of {beta}-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation","volume":"84","author":"Zhan","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S0008-6363(00)00187-5","article-title":"Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart","volume":"48","author":"Du","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2019.01.070","article-title":"Myofibroblast beta2 adrenergic signaling amplifies cardiac hypertrophy in mice","volume":"510","author":"Imaeda","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3389\/fphar.2017.00186","article-title":"A Clinical Perspective of Anti-Fibrotic Therapies for Cardiovascular Disease","volume":"8","author":"Fang","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1161\/CIRCRESAHA.110.223925","article-title":"A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse","volume":"107","author":"Gao","year":"2010","journal-title":"Circ. Res."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Grisanti, L.A., de Lucia, C., Thomas, T.P., Stark, A., Strony, J.T., Myers, V.D., Berretta, R., Yu, D., Sardu, C., and Marfella, R. (2019). Prior beta-blocker treatment decreases leukocyte responsiveness to injury. JCI Insight.","DOI":"10.1172\/jci.insight.99485"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2019.08.011","article-title":"Death receptor 5 contributes to cardiomyocyte hypertrophy through epidermal growth factor receptor transactivation","volume":"136","author":"Tanner","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.yjmcc.2014.02.009","article-title":"beta-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1\/2 and Akt","volume":"72","author":"Grisanti","year":"2014","journal-title":"J. Mol. Cell. Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8507\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:21Z","timestamp":1760178741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,12]]},"references-count":97,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228507"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228507","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,12]]}}}