{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:09:13Z","timestamp":1788480553765,"version":"build-2803163510"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Arrhythmogenic cardiomyopathy is an inherited disorder characterized by fibro-fatty myocardial replacement and ventricular arrhythmias. Although desmosomal mutations such as desmoglein-2 (\n                      <jats:italic toggle=\"yes\">DSG2<\/jats:italic>\n                      ) are well-established causes, the pathogenic mechanisms of specific missense variants remain incompletely defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We generated a physiologically relevant\n                      <jats:italic toggle=\"yes\">Dsg2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">F536C\/F536C<\/jats:italic>\n                      <\/jats:sup>\n                      knock-in mouse model using CRISPR\/Cas9 to mimic the human\n                      <jats:italic toggle=\"yes\">DSG2<\/jats:italic>\n                      p.Phe531Cys mutation. Comprehensive phenotyping included histopathology, immunostaining, transcriptomic profiling, in vitro cardiomyocyte and fibroblast assays, in vivo imaging and ECG analysis, and ex vivo optical mapping. Therapeutic potential was assessed using the PPAR-\u03b3 (peroxisome proliferator-activated receptor gamma) antagonist GW9662.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Dsg2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">F536C\/F536C<\/jats:italic>\n                      <\/jats:sup>\n                      mice developed progressive cardiac hypertrophy, interstitial fibrosis, lipid accumulation, and inducible ventricular arrhythmias following isoproterenol infusion and programmed electrical stimulation. These changes led to severe cardiac dysfunction and reduced survival. Mechanistically, the mutation caused reduced DSG2 and nuclear accumulation of \u03b2-catenin and PPAR-\u03b3, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities. We also identified activation of epicardial epithelial-to-mesenchymal transition and paracrine fibroblast activation via IL-6 (interleukin-6) and PDGF-BB (platelet-derived growth factor-BB) as key contributors to fibrotic remodeling. Optical mapping revealed prolonged and heterogeneous action potential duration, with both reentrant and focal ectopic mechanisms of ventricular tachycardia. Treatment with GW9662 attenuated lipid accumulation, fibrosis, reactive oxygen species production, and arrhythmogenic susceptibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">Dsg2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">F536C\/F536C<\/jats:italic>\n                      <\/jats:sup>\n                      knock-in mouse is a genotype-specific arrhythmogenic cardiomyopathy model that links desmosomal dysfunction to metabolic remodeling, epicardial epithelial-to-mesenchymal transition, and electrophysiological instability. PPAR-\u03b3 inhibition ameliorated structural and arrhythmogenic remodeling, supporting PPAR-\u03b3 as a potential therapeutic target and advancing precision strategies for desmosome-related cardiomyopathies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005434","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:16:13Z","timestamp":1776194173000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting PPAR-\u03b3 Reduces Fibrosis and Arrhythmogenic Remodeling in DSG2-Linked Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1645-1941","authenticated-orcid":true,"given":"Yung-Hsin","family":"Yeh","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine (Y.-H.C.), College of Medicine, Chang Gung University, Taoyuan, 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