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Therefore, extracellular adenosine is generated locally in tissues under conditions such as hypoxia, ischemia, or inflammation. In fact, plasma levels of adenosine in patients with atrial fibrillation (AF) are elevated, which also correlates with an increased density of adenosine A2A receptors (A2ARs) both in the right atrium and in peripheral blood mononuclear cells (PBMCs). The complexity of adenosine-mediated effects in health and disease requires simple and reproducible experimental models of AF. Here, we generate two AF models, namely the cardiomyocyte cell line HL-1 submitted to Anemonia toxin II (ATX-II) and a large animal model of AF, the right atrium tachypaced pig (A-TP). We evaluated the density of endogenous A2AR in those AF models. Treatment of HL-1 cells with ATX-II reduced cell viability, while the density of A2AR increased significantly, as previously observed in cardiomyocytes with AF. Next, we generated the animal model of AF based on tachypacing pigs. In particular, the density of the key calcium regulatory protein calsequestrin-2 was reduced in A-TP animals, which is consistent with the atrial remodelling shown in humans suffering from AF. Likewise, the density of A2AR in the atrium of the AF pig model increased significantly, as also shown in the biopsies of the right atrium of subjects with AF. Overall, our findings revealed that these two experimental models of AF mimicked the alterations in A2AR density observed in patients with AF, making them attractive models for studying the adenosinergic system in AF.<\/jats:p>","DOI":"10.3390\/ijms24043668","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T03:28:46Z","timestamp":1676258926000},"page":"3668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Increased Density of Endogenous Adenosine A2A Receptors in Atrial Fibrillation: From Cellular and Porcine Models to Human Patients"],"prefix":"10.3390","volume":"24","author":[{"given":"H\u00e9ctor","family":"Godoy-Mar\u00edn","sequence":"first","affiliation":[{"name":"Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, 08907 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-988X","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Jim\u00e9nez-S\u00e1bado","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Sant Pau, IIB Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Tarifa","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Sant Pau, IIB Sant Pau, 08025 Barcelona, Spain"},{"name":"Biomedical Research Institute of Barcelona, IIBB-CSIC, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8820-7545","authenticated-orcid":false,"given":"Antonino","family":"Ginel","sequence":"additional","affiliation":[{"name":"Department Cardiac Surgery, Hospital de la Santa Creu i Sant Pau, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0690-7741","authenticated-orcid":false,"given":"Joana Larupa Dos","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Hjorth","family":"Bentzen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5493-3998","authenticated-orcid":false,"given":"Leif","family":"Hove-Madsen","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Sant Pau, IIB Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, 28029 Madrid, Spain"},{"name":"Biomedical Research Institute of Barcelona, IIBB-CSIC, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-3739","authenticated-orcid":false,"given":"Francisco","family":"Ciruela","sequence":"additional","affiliation":[{"name":"Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, 08907 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1161\/01.CIR.0000162461.67140.4C","article-title":"Defective Cardiac Ryanodine Receptor Regulation during Atrial Fibrillation","volume":"111","author":"Vest","year":"2005","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1093\/cvr\/28.9.1385","article-title":"Effects of Adenosine on Atrial Refractoriness and Arrhythmias","volume":"28","author":"Kabell","year":"1994","journal-title":"Cardiovasc. 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