{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:05:14Z","timestamp":1790805914947,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"departmental funding provided to Francesco Squadrito"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-\u03b2 activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-\u03b2 binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production\/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-\u03b2-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-\u03b2 at the concentration of 10 ng\/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-\u03b2 stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 \u00b5M and 1 \u00b5M, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-\u03b2 through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3\/9, BGN, caspase-1 and IL-1\u03b2 gene expression was markedly decreased following A2AR antagonist treatment in TGF-\u03b2-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, \u03b1-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.<\/jats:p>","DOI":"10.3390\/ijms24021784","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T06:03:30Z","timestamp":1673849010000},"page":"1784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts"],"prefix":"10.3390","volume":"24","author":[{"given":"Michele","family":"Scuruchi","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Mannino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Imbesi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4187-2265","authenticated-orcid":false,"given":"Giovanni","family":"Pallio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-8522","authenticated-orcid":false,"given":"Giovanna","family":"Vermiglio","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7594-8520","authenticated-orcid":false,"given":"Gianluca","family":"Bagnato","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letteria","family":"Minutoli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. 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Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715258","DOI":"10.3389\/fcvm.2021.715258","article-title":"Cardiac Fibrosis: Cellular Effectors, Molecular Pathways, and Exosomal Roles","volume":"8","author":"Jiang","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.yjmcc.2015.11.025","article-title":"Mechanical control of cardiac myofibroblasts","volume":"93","author":"Shafieyan","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_3","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. 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