{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:10:09Z","timestamp":1789063809131,"version":"build-2803163510"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction.\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy and\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      mutations. We then studied the fibrogenic responses of cardiac MSCs to TGF\u03b21 (transforming growth factor \u03b21) using Western\/Co-IP, autophagy assays, gene knockdowns\/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      TGF\u03b21 induced excessive accumulation of VIM (vimentin)\/fibrillar collagens and over-activated fibrotic genes in\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      -mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGF\u03b21.\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      -mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (\n                      <jats:italic toggle=\"yes\">COL1A1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">COL3A1<\/jats:italic>\n                      , and fibronectin [\n                      <jats:italic toggle=\"yes\">FN<\/jats:italic>\n                      ]) via heightened p38 activity after TGF\u03b21. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of\n                      <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n                      mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our data reveal that DSP deficiency in MSCs\/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.325512","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:00:19Z","timestamp":1787130019000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Desmoplakin Mutations in Cardiac Fibroblasts Cause TGF\u03b21-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation"],"prefix":"10.1161","volume":"139","author":[{"given":"Chuanyu","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5538-9605","authenticated-orcid":true,"given":"Weinian","family":"Shou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6988-4631","authenticated-orcid":true,"given":"Shing-Fai","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-0803","authenticated-orcid":true,"given":"Ardan M.","family":"Saguner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Center, University Hospital Zurich (A.M.S., C.B., F.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Brunckhorst","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Center, University Hospital Zurich (A.M.S., C.B., F.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4748-0158","authenticated-orcid":true,"given":"Firat","family":"Duru","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Center, University Hospital Zurich (A.M.S., C.B., F.D.)."},{"name":"Center for Integrative Human Physiology, University of Zurich, Switzerland (F.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-5342","authenticated-orcid":true,"given":"Joseph E.","family":"Marine","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (J.E.M., C.A.J., H. 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