{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:41:09Z","timestamp":1786977669694,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,9,21]],"date-time":"2019-09-21T00:00:00Z","timestamp":1569024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2013-02358692"],"award-info":[{"award-number":["GR-2013-02358692"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016990","name":"Beneficentia Stiftung","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100016990","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: The clinical outcome of patients affected by dilated cardiomyopathy (DCM) is heterogeneous, since its pathophysiology is only partially understood. Interleukin 1\u03b2 levels could predict the mortality and necessity of cardiac transplantation of DCM patients. Objective: To investigate mechanisms triggering sterile inflammation in dilated cardiomyopathy (DCM). Methods: Hearts explanted from 62 DCM patients were compared with 30 controls, employing immunohistochemistry, cellular and molecular biology, as well as metabolomics studies. Results: Although misfolded protein accumulation and aggresome formation characterize DCM hearts, aggresomes failed to trigger the autophagy lysosomal pathway (ALP), with consequent accumulation of both p62SQSTM1 and dysfunctional mitochondria. In line, DCM hearts are characterized by accumulation of lipoperoxidation products and activation of both redox responsive pathways and inflammasome. Consistently with the fact that mTOR signaling may impair ALP, we observed, an increase in DCM activation, together with a reduction in the nuclear localization of Transcription Factor EB -TFEB- (a master regulator of lysosomal biogenesis). These alterations were coupled with metabolomic alterations, including accumulation of branched chain amino acids (BCAAs), known mTOR activators. Consistently, reduced levels of PP2Cm, a phosphatase that regulates the key catabolic step of BCAAs, coupled with increased levels of miR-22, a regulator of PP2Cm levels that triggers senescence, characterize DCM hearts. The same molecular defects were present in clinically relevant cells isolated from DCM hearts, but they could be reverted by downregulating miR-22. Conclusion: We identified, in human DCM, a complex series of events whose key players are miR-22, PP2Cm, BCAA, mTOR, and ALP, linking loss of proteostasis with inflammasome activation. These potential therapeutic targets deserve to be further investigated.<\/jats:p>","DOI":"10.3390\/jcm8101519","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T03:26:32Z","timestamp":1569209192000},"page":"1519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Autophagy and Inflammasome Activation in Dilated Cardiomyopathy"],"prefix":"10.3390","volume":"8","author":[{"given":"Angela","family":"Caragnano","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-9905","authenticated-orcid":false,"given":"Aneta","family":"Aleksova","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, Azienda Sanitaria Universitaria di Trieste and Department of Medical Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-4228","authenticated-orcid":false,"given":"Michela","family":"Bulfoni","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Cervellin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene Giulia","family":"Rolle","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Veneziano","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4298-2343","authenticated-orcid":false,"given":"Arianna","family":"Barchiesi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Mimmi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-029X","authenticated-orcid":false,"given":"Carlo","family":"Vascotto","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Finato","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Sponga","sequence":"additional","affiliation":[{"name":"Cardiothoracic Department, Azienda Sanitaria Universitaria Integrata di Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugolino","family":"Livi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Isola","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Di Loreto","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Bussani","sequence":"additional","affiliation":[{"name":"Institute of Pathological Anatomy, Azienda Sanitaria Universitaria di Trieste and Department of Medical Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Sinagra","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, Azienda Sanitaria Universitaria di Trieste and Department of Medical Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0562-7852","authenticated-orcid":false,"given":"Daniela","family":"Cesselli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-2710","authenticated-orcid":false,"given":"Antonio Paolo","family":"Beltrami","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.hlc.2011.07.008","article-title":"Guidelines for the diagnosis and management of familial dilated cardiomyopathy","volume":"20","author":"Fatkin","year":"2011","journal-title":"Heart Lung Circ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1016\/j.jacc.2011.01.015","article-title":"Update 2011: Clinical and genetic issues in familial dilated 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