| First Author | Jiao L | Year | 2019 |
| Journal | Cell Death Dis | Volume | 10 |
| Issue | 12 | Pages | 942 |
| PubMed ID | 31819041 | Mgi Jnum | J:294533 |
| Mgi Id | MGI:6455379 | Doi | 10.1038/s41419-019-2136-6 |
| Citation | Jiao L, et al. (2019) lncRNA-ZFAS1 induces mitochondria-mediated apoptosis by causing cytosolic Ca(2+) overload in myocardial infarction mice model. Cell Death Dis 10(12):942 |
| abstractText | Previously, we have identified ZFAS1 as a potential new long non-coding RNA (lncRNA) biomarker of acute myocardial infarction (MI) and as a sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) inhibitor, causing intracellular Ca(2+) overload and contractile dysfunction in a mouse model of MI. In the current study, we aimed to evaluate the effects of ZFAS1 on the apoptosis of cardiomyocytes in the MI mouse model. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA or siZFAS1 partially abrogated the ischemia-induced apoptosis of cardiomyocytes. Overexpression of ZFAS1 in normal cardiomyocytes reduced the cell viability, similar to that observed in hypoxia-treated cardiomyocytes. Moreover, ZFAS1 cardiac-specific knock-in mice showed impaired cardiac function, adversely altered Ca(2+) homeostasis, repressed expression and activities of SERCA2a, and increased apoptosis. At the subcellular level, ZFAS1 induced mitochondrial swelling and showed a pronounced decrease in mitochondrial membrane potential. At the molecular level, ZFAS1 activated the mitochondria apoptosis pathway, which could be nearly abolished by a calcium chelator. The effects of ZFAS1 were readily reversible upon knockdown of this lncRNA. Notably, ZFAS1-FD (only functional domain) mimicked the effects of full-length ZFAS1 in regulation of cardiomyocyte apoptosis. In conclusion, our study shows that ZFAS1, an endogenous SERCA2a inhibitor, induces mitochondria-mediated apoptosis via cytosolic Ca(2+) overload. Therefore, anti-ZFAS1 might be considered a new therapeutic strategy for protecting cardiomyocytes from MI-induced apoptosis. |
