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Understanding the effects and mechanisms of <jats:italic>PSEN1<\/jats:italic> in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that <jats:italic>PSEN1<\/jats:italic> was downregulated in ischemia\u2010induced failing hearts. Functionally, cardiovascular specific <jats:italic>PSEN1<\/jats:italic> deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11\u2009months, the ratio of the heart weight\/body weight was slightly lower in the <jats:italic>Sm22a\u2010PSEN1<\/jats:italic>\u2010KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the <jats:italic>Sm22a\u2010PSEN1<\/jats:italic>\u2010KO group compared with the percent of these measures in the WT group, indicating that <jats:italic>PSEN1\u2010<\/jats:italic>KO resulted in heart failure. The abnormally regulated genes resulted from <jats:italic>PSEN1<\/jats:italic>\u2010KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca<jats:sup>2+<\/jats:sup> ion channels, promoting us to investigate the effects of <jats:italic>PSEN1<\/jats:italic> KO on regulation of Ca<jats:sup>2+<\/jats:sup> in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, <jats:italic>PSEN1\u2010<\/jats:italic>KO increased the concentration of cytosolic Ca<jats:sup>2+<\/jats:sup> and reduced Ca<jats:sup>2+<\/jats:sup> concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca<jats:sup>2+<\/jats:sup> was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of <jats:italic>PSEN1<\/jats:italic> knockout mice. These results indicate that the process of Ca<jats:sup>2+<\/jats:sup> release from SR into cytoplasm was affected by <jats:italic>PSEN1<\/jats:italic> KO. Therefore, the abnormalities in Ca<jats:sup>2+<\/jats:sup> homeostasis resulted from downregulation of <jats:italic>PSEN1<\/jats:italic> in failing hearts might contribute to aging\u2010related cardiomyopathy, which might had important implications for the treatment of aging\u2010related heart diseases.<\/jats:p>","DOI":"10.1002\/cbin.11753","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T12:07:01Z","timestamp":1640261221000},"page":"475-487","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiovascular\u2010specific <i>PSEN1<\/i> deletion leads to abnormalities in calcium homeostasis"],"prefix":"10.1002","volume":"46","author":[{"given":"Xiao\u2010Wei","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"},{"name":"Department of Physiology Ningxia Medical University Yinchuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing\u2010Ning","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Biophysics Second Military Medical University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen\u2010Yu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biophysics Second Military Medical University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Biophysics Second Military Medical University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya\u2010Feng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Biophysics Second Military Medical University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song\u2010Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong\u2010Ji","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biophysics Second Military Medical University Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian\u2010Xian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology Changhai Hospital Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5298-6383","authenticated-orcid":false,"given":"Shu\u2010Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Physiology Ningxia Medical University Yinchuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"issue":"61073","key":"e_1_2_10_2_1","first-page":"1","article-title":"Kanisicak O. 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