{"corpus_id":30737109,"paper_sha":"0951d3fac6c447f2b1a4478856ecfd5a4db08111","doi":"10.1111/j.1752-8062.2008.00027.x","arxiv_id":null,"pmid":20354569,"pmcid":"PMC2846643","mag_id":2141472937,"dblp_id":null,"acl_id":null,"title":"Cardiac‐Restricted Overexpression of the A2A‐Adenosine Receptor in FVB Mice Transiently Increases Contractile Performance and Rescues the Heart Failure Phenotype in Mice Overexpressing the A1‐Adenosine Receptor","year":2008,"publication_date":"2008-09-01","venue":"Clinical and Translational Science","journal":{"name":"Clinical and Translational Science","pages":null,"volume":"1"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":30,"citation_count":23,"influential_citation_count":2,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Biological Transport","mj":false,"ui":"D001692"},{"d":"Calcium","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D002118"},{"d":"Cardiomyopathies","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"physiopathology","mj":false,"ui":"Q000503"}],"ui":"D009202"},{"d":"Heart Failure","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"physiopathology","mj":true,"ui":"Q000503"}],"ui":"D006333"},{"d":"Heart Function Tests","mj":false,"ui":"D006334"},{"d":"Hemodynamics","mj":false,"ui":"D006439"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Mice, Transgenic","mj":false,"ui":"D008822"},{"d":"Myocardial Contraction","mj":false,"qs":[{"q":"physiology","mj":true,"ui":"Q000502"}],"ui":"D009200"},{"d":"Myocardium","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":true,"ui":"Q000473"}],"ui":"D009206"},{"d":"Organ Specificity","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D009928"},{"d":"Phenotype","mj":false,"ui":"D010641"},{"d":"Receptor, Adenosine A1","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D043682"},{"d":"Receptor, Adenosine A2A","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D043705"},{"d":"Signal Transduction","mj":false,"ui":"D015398"},{"d":"Time Factors","mj":false,"ui":"D013997"},{"d":"Transgenes","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D019076"}],"chemicals":[{"n":"Receptor, Adenosine A1","ui":"D043682","reg":"0"},{"n":"Receptor, Adenosine A2A","ui":"D043705","reg":"0"},{"n":"Calcium","ui":"D002118","reg":"SY7Q814VUP"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1752-8062.2008.00027.x","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/0951d3fac6c447f2b1a4478856ecfd5a4db08111","s2_open_access_license":"unspecified-oa","s2_open_access_status":"HYBRID","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"In the heart, adenosine binds to pharmacologically distinct G‐protein‐coupled receptors (A1‐R, A2A‐R, and A3‐R). While the role of A1‐and A3‐Rs in the heart has been clarifed, the effect of genetically manipulating the A2A‐R has not been defned. Thus, we created mice overexpressing a cardiac‐restricted A2A‐R transgene. Mice with both low (Lo) and high (Hi) levels of A2A‐R overexpression demonstrated an increase in cardiac contractility at 12 weeks. These changes were associated with a signifcantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, and a signifcantly enhanced sarcoplasmic reticulum Ca2+ uptake activity. At 20 weeks, the effects of A2A‐R overexpression on cardiac contractility diminished. The positive effects elicited by A2A‐R overexpression differ from the heart failure phenotype we observed with A1‐R overexpresson. Interestingly, coexpression of A2A‐R TGHi, but not A2A‐R TGLo, enhanced survival, prevented the development of left ventricular dysfunction and heart failure, and improved Ca2+ handling in mice overexpressing the A1‐R. These results suggest that adenosine‐mediated signaling in the heart requires a balance between A1‐ and A2A‐Rs—a fnding that may have important implications for the ongoing clinical evaluation of adenosine receptor subtype‐specifc agonists and antagonists for the treatment of cardiovascular diseases.","claims":[{"public_id":"cl_ac33f7b968f157047211e5d36e68a949","status":"active","text":"Adenosine-mediated cardiac signaling requires a balance between A1-adenosine receptor and A2A-adenosine receptor activity.","confidence":0.85,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/claims/cl_ac33f7b968f157047211e5d36e68a949"},{"public_id":"cl_3b8c497f39e0a8c6bd6306ab54f6d740","status":"active","text":"At 20 weeks, the positive effects of cardiac A2A-adenosine receptor overexpression on cardiac contractility diminished.","confidence":0.9,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/claims/cl_3b8c497f39e0a8c6bd6306ab54f6d740"},{"public_id":"cl_98c8f3720625ee478ca81a29fcf43692","status":"active","text":"Coexpression of high-level but not low-level A2A-adenosine receptor transgene enhanced survival, prevented left ventricular dysfunction and heart failure phenotype, and improved Ca2+ handling in mice overexpressing the A1-adenosine receptor.","confidence":0.95,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/claims/cl_98c8f3720625ee478ca81a29fcf43692"},{"public_id":"cl_d9e3a066ee07c958cab3b21dbb2fa881","status":"active","text":"Mice with both low and high levels of cardiac A2A-adenosine receptor overexpression demonstrated increased cardiac contractility at 12 weeks, associated with higher systolic intracellular calcium concentration, higher maximal contraction amplitude, and enhanced sarcoplasmic reticulum Ca2+ uptake.","confidence":0.92,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/claims/cl_d9e3a066ee07c958cab3b21dbb2fa881"}],"concepts":[{"public_id":"co_221d8e4a4fec4cab4096c425817a72d8","status":"active","name":"A1-adenosine receptor","description":"A G-protein-coupled adenosine receptor subtype in the heart whose overexpression in mice produces a heart failure phenotype.","types":["receptor"],"aliases":["A1-R"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_221d8e4a4fec4cab4096c425817a72d8"},{"public_id":"co_3628eb817921e863ea05727551cbd4bf","status":"active","name":"Ca2+ handling","description":"The cellular mechanisms regulating intracellular calcium dynamics in cardiomyocytes, improved by high-level A2A-R coexpression in A1-R overexpressing mice.","types":["cellular process"],"aliases":["calcium handling"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_3628eb817921e863ea05727551cbd4bf"},{"public_id":"co_619cf0c007797d812a36f1739d47950f","status":"active","name":"maximal contraction amplitude","description":"The peak magnitude of cardiomyocyte shortening measured in this study, found to be higher in A2A-R overexpressing mice at 12 weeks.","types":["measurement"],"aliases":[],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_619cf0c007797d812a36f1739d47950f"},{"public_id":"co_63d47e8af1beee03693e02507d074a07","status":"active","name":"systolic intracellular calcium concentration","description":"The peak intracellular calcium level during systole, measured as significantly elevated in A2A-R overexpressing mice.","types":["measurement"],"aliases":["systolic [Ca2+]i"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_63d47e8af1beee03693e02507d074a07"},{"public_id":"co_70a2ca4366aacb3baa1abed4a71da9d7","status":"active","name":"cardiac-restricted A2A-R transgene","description":"A transgenic construct driving overexpression of the A2A-adenosine receptor specifically in heart tissue, generated at low (TGLo) and high (TGHi) expression levels.","types":["genetic construct"],"aliases":["A2A-R TGLo","A2A-R TGHi"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_70a2ca4366aacb3baa1abed4a71da9d7"},{"public_id":"co_733f313615b51643bdf919b2ca697d92","status":"active","name":"left ventricular dysfunction","description":"Impaired contractile function of the left ventricle, a cardiac pathology whose development was prevented by high-level A2A-R coexpression.","types":["cardiac condition"],"aliases":["LV dysfunction"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_733f313615b51643bdf919b2ca697d92"},{"public_id":"co_8fd79cb64d35747a48da2eaeea97ed31","status":"active","name":"cardiac contractility","description":"The intrinsic ability of the heart muscle to contract, measured here in A2A-R transgenic mice at 12 and 20 weeks post-creation.","types":["physiological measure"],"aliases":[],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_8fd79cb64d35747a48da2eaeea97ed31"},{"public_id":"co_9614f578e8a7e2b51396b0d6ce22dc80","status":"active","name":"sarcoplasmic reticulum Ca2+ uptake","description":"The rate at which the sarcoplasmic reticulum sequesters calcium ions from the cardiomyocyte cytoplasm, measured as enhanced in A2A-R overexpressing mice.","types":["cellular process"],"aliases":["SR Ca2+ uptake","sarcoplasmic reticulum Ca2+ uptake activity"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_9614f578e8a7e2b51396b0d6ce22dc80"},{"public_id":"co_d858053bde10fbc6ffc65ef3215526d1","status":"active","name":"A2A-adenosine receptor","description":"A pharmacologically distinct G-protein-coupled receptor subtype for adenosine expressed in the heart, studied here via cardiac-restricted transgenic overexpression.","types":["receptor"],"aliases":["A2A-R"],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_d858053bde10fbc6ffc65ef3215526d1"},{"public_id":"co_f2cafa3a31f2ce956b65cad5c6a217d3","status":"active","name":"heart failure phenotype","description":"The pathological cardiac state produced by A1-adenosine receptor overexpression in mice, characterized by ventricular dysfunction and reduced survival.","types":["disease phenotype"],"aliases":[],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_f2cafa3a31f2ce956b65cad5c6a217d3"},{"public_id":"co_f4088d01b397e9911ed0c25702e84562","status":"active","name":"FVB mice","description":"The inbred mouse strain used as the genetic background for generating cardiac A2A-R transgenic animals in this study.","types":["animal model"],"aliases":[],"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"},{"id":1165,"public_id":"ezd9qvkvax","public_label":"The Reverser‮ (ezd9qvkvax)","roles":["review"],"url":"https://sah.borca.ai/u/ezd9qvkvax"}],"url":"https://sah.borca.ai/concepts/co_f4088d01b397e9911ed0c25702e84562"}],"external_ids":{"DOI":"10.1111/j.1752-8062.2008.00027.x","ArXiv":null,"PubMed":20354569,"PubMedCentral":"PMC2846643","MAG":2141472937,"DBLP":null,"ACL":null},"open_access":{"is_open_access":true,"pdf_url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1752-8062.2008.00027.x","landing_url":"https://www.semanticscholar.org/paper/0951d3fac6c447f2b1a4478856ecfd5a4db08111","source":"semantic_scholar","pdf_url_source":"semantic_scholar_open_access_pdf","license":"unspecified-oa","status":"HYBRID","reason":null},"reference_availability":{"status":"available","references_indexed":true,"full_text_available":false,"full_text_source":null,"count_basis":"semantic_scholar_metadata","extraction_status":"not_applicable","reason":null},"source":{"provider":"episteme2","base_corpus":"semantic_scholar_dump","freshness_mode":"unknown","basis":["semantic_scholar_metadata","postgres_metadata"],"limits":["paper metadata is based on indexed upstream scholarly datasets","claims and concepts are available only for extracted papers","absence of claims or concepts means no extracted graph data is available in this response"],"status":"available","degraded":false,"degraded_reasons":[],"diagnostics":{"status":"available","degraded":false,"degraded_reasons":[],"metadata_status":"available","graph_status":"available","abstract_status":"available"},"source_flags":5},"paper_id":631820,"paper_uid":"68730ca2-89b8-44d1-829c-4060b375b67f","canonical_identity":{"paper_id":631820,"paper_uid":"68730ca2-89b8-44d1-829c-4060b375b67f","identity_status":"available","lookup_basis":"semantic_scholar_external_id","compatibility_path":"corpus_id"},"url":"https://sah.borca.ai/papers/30737109"}