期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 25, 期 -, 页码 638-651出版社
CELL PRESS
DOI: 10.1016/j.omtn.2021.08.006
关键词
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资金
- Natural Science Foundation of Shandong Province [ZR2019BH014]
- National Natural Science Foundation of China [82050410450, 81850410551, 91849209]
CMDL-1 may exert an anti-apoptotic role in DOX cardiotoxicity by regulating Drp1 S637 phosphorylation and play a crucial role in mitochondrial dynamics.
Doxorubicin (DOX)-induced cardiotoxicity has been one of the major limitations for its clinical use. Although extensive studies have been conducted to decipher the molecular mechanisms underlying DOX cardiotoxicity, no effective preventive or therapeutic measures have yet been identified. Microarray analysis showed that multiple long non-coding RNAs (lncRNAs) are differentially expressed between control- and DOX-treated cardiomyocytes. Functional enrichment analysis indicated that the differentially expressed genes are annotated to cardiac hypertrophic pathways. Among differentially expressed lncRNAs, cardiomyocyte mitochondrial dynamicrelated lncRNA 1 (CMDL-1) is the most significantly downregulated lncRNA in cardiomyocytes after DOX exposure. The protein-RNA interaction analysis showed that CMDL-1 may target dynamin-related protein 1 (Dip1). Mechanistic analysis shows that lentiviral overexpression of CMDL-1 prevents DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. However, overexpression of CMDL-1 cannot effectively reduce mitochondrial fission when Drp1 is minimally expressed by small interfering RNA Drp1 (siDrpl). Overexpression of CMDL-1 promotes the association between CMDL-1 and Drp1, as well as with phosphorylated (p-)Drp1, as evidenced by RNA immunoprecipitation analysis. These data indicate the role of CMDL-1 in posttranslational modification of a target protein via regulating its phosphorylation. Collectively, our data indicate that CMDL-1 may play an anti-apoptotic role in DOX cardiotoxicity by regulating Drp1 S637 phosphorylation. Thus, CMDL-1 may serve as a potential therapeutic target in DOX cardiotoxicity.
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