CircRNA CDR1as promotes cardiomyocyte apoptosis through activating hippo signaling pathway in diabetic cardiomyopathy

• Published in: European journal of pharmacology 2022-05, Vol.922, p.174915-174915, Article 174915
• Main Authors: Shao, Yingchun, Li, Mengmeng, Yu, Qi, Gong, Manyu, Wang, Yanying, Yang, Xuewen, Liu, Liheng, Liu, Dongping, Tan, Zhongyue, Zhang, Yuanyuan, Qu, Yunmeng, Li, Haodong, Wang, Yaqi, Jiao, Lei, Zhang, Ying
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; CDR1as; Diabetes Mellitus - metabolism; Diabetic Cardiomyopathies - genetics; Diabetic Cardiomyopathies - metabolism; Diabetic cardiomyopathy; Hippo; Hippo Signaling Pathway; Humans; m6A; Mammals - genetics; Mice; Myocytes, Cardiac - metabolism; RNA, Circular - genetics; Signal Transduction; Transcription Factors - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2022.174915

Diabetic cardiomyopathy (DCM), as a major complication of diabetic patients, can cause myocardial metabolic remodeling and lead to severe and irreversible cardiac dysfunction. Previously, we found that the circular RNA cerebellar degeneration-related protein 1 antisense (Circ-CDR1as) independently predicted acute myocardial infarction (AMI) and might be a new indicator marker for this. However, CDR1as was not clearly described in diabetic cardiomyopathy. Therefore, our purpose was to deeply explore the function of CDR1as in DCM. In this study, we found that CDR1as was upregulated in DCM, and knockdown of CDR1as could improve the apoptosis caused by DCM. Mechanistically, CDR1as activates the Hippo signaling pathway by significantly inhibiting Mammalian sterile 20-like kinase 1 (MST1) ubiquitination level. Furthermore, as a transcriptional factor of CDR1as, Forkhead box group O3a (FOXO3) was identified to activate the Hippo signaling pathway. Notably, the total m6A level was downregulated in the cardiac tissue of DCM. Alk B homolog 5 (ALKBH5), a m6A demethylation enzyme, was upregulated in the cardiomyocytes of DCM mice and posttranscriptionally activated FOXO3 by m6A demethylation in an m6A-YTHDF2-dependent manner. Hence, our work reveals the key function of the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway in DCM and provides insight into the critical roles of m6A methylation in DCM. The ALKBH5-FOXO3 m6A-FOXO3 mRNA-CDR1as/Hippo signaling pathway is activated in the diabetic cardiomyopathy mouse model. Schematic diagram depicting the mechanism of CDR1as promotes cardiomyocyte apoptosis through activating Hippo signaling pathway in diabetic cardiomyopathy as follows: DCM→ALKBH5↑→FOXO3 m6A↓→FOXO3↑→CDR1as↑→MST1 ubiquitination level↓→MST1↑→p-YAP↑→cardiomyocyte apoptosis↑, and ALKBH5 posttranscriptionally activated FOXO3 by m6A demethylation in a m6A-YTHDF2-dependent manner, thus silencing this signaling pathway may be a promising new treatment for diabetic cardiomyopathy. [Display omitted]