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The present study aimed to test the hypothesis that chronic negative stress leads to alterations in DNA methylation of certain cardiac genes, which in turn contribute to pathologic remodeling of the heart. We found that mice that were exposed to chronic restraint stress (CRS) for 4 wk exhibited cardiac remodeling toward heart failure, as characterized by ventricular chamber dilatation, wall thinning, and decreased contractility. CRS also induced cardiac arrhythmias, including intermittent sinus tachycardia and bradycardia, frequent premature ventricular contraction, and sporadic atrioventricular conduction block. Circulating levels of stress hormones were elevated, and the cardiac expression of tyrosine hydroxylase, a marker of sympathetic innervation, was increased in CRS mice. Using reduced representation bisulfite sequencing, we found that although CRS did not lead to global changes in DNA methylation in the murine heart, it nevertheless altered methylation at specific genes that are associated with the dilated cardiomyopathy (DCM) (\n                    <jats:italic>e.g.<\/jats:italic>\n                    , desmin) and adrenergic signaling of cardiomyocytes (ASPC) (\n                    <jats:italic>e.g.<\/jats:italic>\n                    , adrenergic receptor\u2010\u03b11) pathways. We conclude that CRS induces cardiac remodeling and arrhythmias, potentially through altered methylation of myocardial genes associated with the DCM and ASPC pathways.\u2014Zhang P., Li, T., Liu, Y.\u2010Q., Zhang, H., Xue, S.\u2010M., Li, G., Cheng, H.\u2010Y.M., Cao, J.\u2010M. Contribution of DNA methylation in chronic stress\u2010induced cardiac remodeling and arrhythmias in mice. FASEB J. 33, 12240\u201012252 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201900100r","type":"journal-article","created":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T20:36:31Z","timestamp":1566333391000},"page":"12240-12252","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Contribution of DNA methylation in chronic stress\u2010induced cardiac remodeling and arrhythmias in mice"],"prefix":"10.1096","volume":"33","author":[{"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Research Key Laboratory of Medical Electrophysiology, Ministry of Education\u2010Medical Electrophysiological Key Laboratory of Sichuan Province Southwest Medical University Luzhou China"},{"name":"Collaborative Innovation 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