期刊
CELL DEATH AND DIFFERENTIATION
卷 29, 期 4, 页码 709-721出版社
SPRINGERNATURE
DOI: 10.1038/s41418-021-00885-x
关键词
-
资金
- Natural Science Foundation of Jiangsu Province
This study identified the circ-SNRK - miR-33 - SNRK axis regulating energy metabolism in cardiomyocytes, and breaking the negative feedback loop of SNRK to circ-SNRK can improve cardiac function post-myocardial infarction, suggesting a potential therapeutic target for heart failure.
A limited delivery of oxygen and metabolic substrate to the heart caused by myocardial infarction (MI) impairs the cardiac function, and often results in heart failure. Here, we identified a circRNA (circ-SNRK) from SNRK (sucrose nonfermenting 1-related kinase, which can increase the cardiac mitochondrial efficiency) in cardiomyocytes (CMs). Circ-SNRK can sponge the miR-33 and in turn improved the ATP synthesis via SNRK, proving the existence of circ-SNRK - miR-33 - SNRK axis. Furthermore, we found that protein NOVA1 (NOVA alternative splicing regulator 1) could accelerate the circ-SNRK formation; a cleaved peptide (similar to 55 kDa) from SNRK enters the nucleus and blocks the cyclization of circ-SNRK via binding to NOVA1. The aforementioned negative feedback of SNRK to circ-SNRK limited the SNRK at a proper level, and inhibited the protective role of circ-SNRK in ischemic heart. In addition, our in vivo experiment indicated that the overexpression of exogenic circ-SNRK could break this loop and improves the cardiac function post-MI in rats. Together, our results demonstrated that the negative loop of circ-SNRK with SNRK regulates the energy metabolism in CMs, thus might be a potential therapeutic target for heart failure.
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