{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:41:41Z","timestamp":1791639701272,"version":"4.3.4"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Else-Kroener-Fresenius Foundation","award":["2022_EKEA.43"],"award-info":[{"award-number":["2022_EKEA.43"]}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["Exc2026-1"],"award-info":[{"award-number":["Exc2026-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["456687919"],"award-info":[{"award-number":["456687919"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Robert Schwiete Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We used single-nuclei RNA sequencing with human tissues from two samples of one healthy donor, and five hypertrophic and two failing hearts. Unsupervised sub-clustering of 7110 nuclei led to the identification of 7 distinct fibroblast clusters. De-convolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a pro-fibrotic extra-cellular matrix composition in patients with established cardiac hypertrophy and heart failure. This sub-cluster was characterized by high expression of POSTN, RUNX1, CILP, and a target gene adipocyte enhancer-binding protein 1 (AEBP1) (all P &amp;lt; 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (P &amp;lt; 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA-mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, and fibroblast contractile capacity and \u03b1-SMA gene expression, which is a hallmark of fibroblast activation (all P &amp;lt; 0.05). Mechanistically, the anti-fibrotic effects of AEBP1 silencing were linked to transforming growth factor-beta pathway modulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvad140","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:10:59Z","timestamp":1693296659000},"page":"2550-2562","source":"Crossref","is-referenced-by-count":41,"title":["Single-nuclear transcriptome profiling identifies persistent fibroblast activation in hypertrophic and failing human hearts of patients with longstanding disease"],"prefix":"10.1093","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1324-5536","authenticated-orcid":false,"given":"Badder","family":"Kattih","sequence":"first","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"Goethe University Frankfurt, University Hospital, Department of Cardiology , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicitas","family":"Boeckling","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"Goethe University Frankfurt, University Hospital, Department of Cardiology , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Shumliakivska","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-576X","authenticated-orcid":false,"given":"Lukas","family":"Tombor","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Rasper","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0487-4373","authenticated-orcid":false,"given":"Jedrzej","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"},{"name":"Goethe University Frankfurt, University Hospital, Centre for Cardiovascular Imaging, Institute of Experimental and Translational Cardiovascular Imaging , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luka","family":"Nicin","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley T","family":"Abplanalp","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C","family":"Carstens","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mani","family":"Arsalan","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, University Hospital , Department of Cardiovascular Surgery, Theodor-Stern-Kai 7, Frankfurt 60590 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Emrich","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, University Hospital , Department of Cardiovascular Surgery, Theodor-Stern-Kai 7, Frankfurt 60590 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Holubec","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, University Hospital , Department of Cardiovascular Surgery, Theodor-Stern-Kai 7, Frankfurt 60590 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-8949","authenticated-orcid":false,"given":"Thomas","family":"Walther","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, University Hospital , Department of Cardiovascular Surgery, Theodor-Stern-Kai 7, Frankfurt 60590 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina O","family":"Puntmann","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"},{"name":"Goethe University Frankfurt, University Hospital, Centre for Cardiovascular Imaging, Institute of Experimental and Translational Cardiovascular Imaging , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6044-950X","authenticated-orcid":false,"given":"Eike","family":"Nagel","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , Germany"},{"name":"Goethe University Frankfurt, University Hospital, Centre for Cardiovascular Imaging, Institute of Experimental and Translational Cardiovascular Imaging , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3217-5449","authenticated-orcid":false,"given":"David","family":"John","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt, Institute for Cardiovascular Regeneration , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany"},{"name":"German Centre for Cardiovascular Research , Partner Site Rhine-Main, 60590 Frankfurt am Main , 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