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In the current study, we aimed to evaluate the effects of <jats:italic>ZFAS1<\/jats:italic> on the apoptosis of cardiomyocytes in the MI mouse model. Knockdown of endogenous <jats:italic>ZFAS1<\/jats:italic> by virus-mediated silencing shRNA or si<jats:italic>ZFAS1<\/jats:italic> partially abrogated the ischemia-induced apoptosis of cardiomyocytes. Overexpression of <jats:italic>ZFAS1<\/jats:italic> in normal cardiomyocytes reduced the cell viability, similar to that observed in hypoxia-treated cardiomyocytes. Moreover, <jats:italic>ZFAS1<\/jats:italic> cardiac-specific knock-in mice showed impaired cardiac function, adversely altered Ca<jats:sup>2+<\/jats:sup> homeostasis, repressed expression and activities of SERCA2a, and increased apoptosis. At the subcellular level, <jats:italic>ZFAS1<\/jats:italic> induced mitochondrial swelling and showed a pronounced decrease in mitochondrial membrane potential. At the molecular level, <jats:italic>ZFAS1<\/jats:italic> activated the mitochondria apoptosis pathway, which could be nearly abolished by a calcium chelator. The effects of <jats:italic>ZFAS1<\/jats:italic> were readily reversible upon knockdown of this lncRNA. Notably, <jats:italic>ZFAS1-FD<\/jats:italic> (only functional domain) mimicked the effects of full-length <jats:italic>ZFAS1<\/jats:italic> in regulation of cardiomyocyte apoptosis. In conclusion, our study shows that <jats:italic>ZFAS1<\/jats:italic>, an endogenous SERCA2a inhibitor, induces mitochondria-mediated apoptosis via cytosolic Ca<jats:sup>2+<\/jats:sup> overload. Therefore, anti-<jats:italic>ZFAS1<\/jats:italic> might be considered a new therapeutic strategy for protecting cardiomyocytes from MI-induced apoptosis.<\/jats:p>","DOI":"10.1038\/s41419-019-2136-6","type":"journal-article","created":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T16:03:22Z","timestamp":1575907402000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca2+ overload in myocardial infarction mice model"],"prefix":"10.1038","volume":"10","author":[{"given":"Lei","family":"Jiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyue","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Xuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqiu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,9]]},"reference":[{"key":"2136_CR1","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.tcm.2017.07.011","volume":"28","author":"Y Castro-Dominguez","year":"2018","unstructured":"Castro-Dominguez, Y., Dharmarajan, K. & McNamara, R. 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