Circular RNA-circPan3 attenuates cardiac hypertrophy via miR-320-3p/HSP20 axis.
Circular RNA-circPan3 attenuates cardiac hypertrophy via miR-320-3p/HSP20 axis.
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DOI：
10.1186/s11658-023-00520-2
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发表时间：
2024-01-03
影响因子：
8.3
通讯作者：
中科院分区：
文献类型：
--
作者：
环状RNA在心脏组织中富集，在心脏疾病的发病机制中起重要作用。在这项研究中，我们的目的是研究一个保守的心脏富集的circRNA，circPan 3，在心肌肥厚的调节机制。异丙肾上腺素诱导心肌肥厚。通过肌节组织染色、细胞表面积测量和心肌肥大标志物的表达水平来评估心肌细胞肥大的进展。RNA相互作用通过RNA下拉试验检测，甲基化RNA免疫沉淀用于检测m6 A水平。在异丙肾上腺素诱导的心肌肥厚模型中，circPan 3的表达下调。强制表达circPan 3减弱心肌细胞肥大，而抑制circPan 3加重心肌细胞肥大。在机制上，circPan 3是miR-320- 3 p的内源性海绵，而不影响miR-320- 3 p水平。它通过与miR-320- 3 p的内源性相互作用来提高HSP 20的表达。此外，circPan 3被N6甲基化。通过异丙肾上腺素的刺激下调m6 A擦除器ALKBH 5，导致N6-甲基化和circPan 3的不稳定。我们的研究首次报道了circPan 3在心肌细胞中具有抗肥大作用，并揭示了一种新的circPan 3调节的信号通路参与心脏肥大。CircPan 3通过靶向miR-320- 3 p/HSP 20轴抑制心脏肥大，并受ALKBH 5介导的N6-甲基化调节。这一通路可能为心肌肥厚提供潜在的治疗靶点。
Circular RNAs are enriched in cardiac tissue and play important roles in the pathogenesis of heart diseases. In this study, we aimed to investigate the regulatory mechanism of a conserved heart-enriched circRNA, circPan3, in cardiac hypertrophy. Cardiac hypertrophy was induced by isoproterenol. The progression of cardiomyocyte hypertrophy was assessed by sarcomere organization staining, cell surface area measurement, and expression levels of cardiac hypertrophy markers. RNA interactions were detected by RNA pull-down assays, and methylated RNA immunoprecipitation was used to detect m6A level. The expression of circPan3 was downregulated in an isoproterenol-induced cardiac hypertrophy model. Forced expression of circPan3 attenuated cardiomyocyte hypertrophy, while inhibition of circPan3 aggravated cardiomyocyte hypertrophy. Mechanistically, circPan3 was an endogenous sponge of miR-320-3p without affecting miR-320-3p levels. It elevated the expression of HSP20 by endogenously interacting with miR-320-3p. In addition, circPan3 was N6-methylated. Stimulation by isoproterenol downregulated the m6A eraser ALKBH5, resulting in N6-methylation and destabilization of circPan3. Our research is the first to report that circPan3 has an antihypertrophic effect in cardiomyocytes and revealed a novel circPan3-modulated signalling pathway involved in cardiac hypertrophy. CircPan3 inhibits cardiac hypertrophy by targeting the miR-320-3p/HSP20 axis and is regulated by ALKBH5-mediated N6-methylation. This pathway could provide potential therapeutic targets for cardiac hypertrophy.
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