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Interstitial fibrosis has been identified as a central pathophysiological factor induced and maintained by metabolic stress and chronic inflammation. Considering the limited treatment options for cardiac fibrosis, new therapeutic targets are urgently needed. Mounting evidence for the cardioprotective effects of the neuropeptide pituitary adenylate cyclase\u2010activating peptide (PACAP) provides a rationale to elucidate its role and that of its receptor PAC1 in metabolic stress\u2010mediated cardiac fibrosis. Metabolic stress was induced by feeding a cholesterol\u2010enriched diet (CED) to PACAP\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    , PAC1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice and cardiac tissue subjected to analyses of fibrosis. Under CED feeding, a statistically significant (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.001) increase in myocardial fibrosis was observed in PACAP\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and PAC1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    compared to ApoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. These findings suggest a role for PACAP signaling in the mitigation of metabolically induced cardiac fibrosis. The antifibrotic effect of PACAP is dependent on the expression of the PAC1 receptor and only emerges under metabolic stress conditions. PAC1 receptor agonists may have the potential to attenuate metabolically triggered cardiac fibrosis arising after a chronic high\u2010fat diet.\n                  <\/jats:p>","DOI":"10.1111\/jne.70118","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:13:55Z","timestamp":1764141235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiac fibrosis induced by high\u2010fat diet in\n                    <scp>ApoE<\/scp>\n                    \u2010deficient male mice is exacerbated by genetic deletion of\n                    <scp>PACAP<\/scp>\n                    \u2013\n                    <scp>PAC1<\/scp>\n                    signaling"],"prefix":"10.1111","volume":"38","author":[{"given":"J. M.","family":"Schubart","sequence":"first","affiliation":[{"name":"Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3554-2356","authenticated-orcid":false,"given":"M. K. H.","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty Philipps University Marburg  Marburg Germany"},{"name":"Center for Mind, Brain and Behavior Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. A.","family":"Bonaterra","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Mey","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Schwarzbach","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Pankuweit","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital Marburg Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0526-7989","authenticated-orcid":false,"given":"F.","family":"Ausbuettel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital Marburg Philipps University Marburg  Marburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7524-944X","authenticated-orcid":false,"given":"L. 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