Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China.
Eur J Pharmacol. 2022 May 5;922:174915. doi: 10.1016/j.ejphar.2022.174915. Epub 2022 Mar 24.
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.
糖尿病心肌病（DCM）作为糖尿病患者的主要并发症，可导致心肌代谢重构，引起严重且不可逆转的心脏功能障碍。此前，我们发现环状 RNA 小脑退化相关蛋白 1 反义（Circ-CDR1as）可独立预测急性心肌梗死（AMI），可能是该病的一个新指标标志物。然而，在糖尿病心肌病中，CDR1as 的作用并不明确。因此，我们的目的是深入探讨 CDR1as 在 DCM 中的功能。在这项研究中，我们发现 CDR1as 在 DCM 中上调，敲低 CDR1as 可改善 DCM 引起的细胞凋亡。在机制上，CDR1as 通过显著抑制哺乳动物无翅型 MM 相关物 20 样激酶 1（MST1）泛素化水平来激活 Hippo 信号通路。此外，作为 CDR1as 的转录因子，叉头框蛋白 O3a（FOXO3）被鉴定为激活 Hippo 信号通路。值得注意的是，DCM 心脏组织中的总 m6A 水平下调。m6A 去甲基化酶 Alk B 同源物 5（ALKBH5）在 DCM 小鼠的心肌细胞中上调，并通过 m6A 去甲基化以 m6A-YTHDF2 依赖的方式在后转录水平激活 FOXO3。因此，我们的工作揭示了 ALKBH5-FOXO3-CDR1as/Hippo 信号通路在 DCM 中的关键作用，并深入了解了 m6A 甲基化在 DCM 中的关键作用。
