{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:00:26Z","timestamp":1791356426181,"version":"4.3.1"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-153400"],"award-info":[{"award-number":["PJT-153400"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Translational Biology and Engineering Program","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ted Rogers Centre","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,9]]},"abstract":"<jats:p>The prognosis and treatment outcomes of heart failure (HF) patients rely heavily on disease etiology, yet the majority of underlying signaling mechanisms are complex and not fully elucidated. Phosphorylation is a major point of protein regulation with rapid and profound effects on the function and activity of protein networks. Currently, there is a lack of comprehensive proteomic and phosphoproteomic studies examining cardiac tissue from HF patients with either dilated dilated cardiomyopathy (DCM) or ischemic\u00a0cardiomyopathy (ICM). Here, we used a combined proteomic and phosphoproteomic approach to identify and quantify more than 5,000 total proteins with greater than 13,000 corresponding phosphorylation sites across explanted left ventricle (LV) tissue samples, including HF patients with DCM vs. nonfailing controls (NFC), and left ventricular infarct vs. noninfarct, and periinfarct vs. noninfarct regions of HF patients with ICM. Each pair-wise comparison revealed unique global proteomic and phosphoproteomic profiles with both shared and etiology-specific perturbations. With this approach, we identified a DCM-associated hyperphosphorylation cluster in the cardiomyocyte intercalated disc (ICD) protein, \u03b1T-catenin (CTNNA3). We demonstrate using both ex\u00a0vivo isolated cardiomyocytes and in\u00a0vivo using an AAV9-mediated overexpression mouse model, that CTNNA3 phosphorylation at these residues plays a key role in maintaining protein localization at the cardiomyocyte ICD to regulate conductance and cell\u2013cell adhesion. Collectively, this integrative proteomic\/phosphoproteomic approach identifies region- and etiology-associated signaling pathways in human HF and describes a role for CTNNA3 phosphorylation in the pathophysiology of DCM.<\/jats:p>","DOI":"10.1073\/pnas.2212118120","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:11:27Z","timestamp":1682953887000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":40,"title":["Proteomics and phosphoproteomics of failing human left ventricle identifies dilated cardiomyopathy-associated phosphorylation of CTNNA3"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1748-0501","authenticated-orcid":false,"given":"Cristine\u00a0J.","family":"Reitz","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1M8"},{"name":"Translational Biology and Engineering 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Toronto, Toronto, ON M5S 1M8"},{"name":"Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON M5G 1M1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Hadipour-Lakmehsari","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1M8"},{"name":"Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON M5G 1M1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter\u00a0H.","family":"Backx","sequence":"additional","affiliation":[{"name":"Department of Biology, York University, Toronto, ON M3J 1P3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Emili","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118"},{"name":"Department of Biology, Boston University School of Medicine, Boston, MA 02118"},{"name":"The Centre for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9154-9028","authenticated-orcid":false,"given":"Gavin\u00a0Y.","family":"Oudit","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, AB T6G 2B7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3502-6986","authenticated-orcid":false,"given":"Uros","family":"Kuzmanov","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1M8"},{"name":"Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON M5G 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