lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis

Abstract

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

Keywords

lncR-GAS5 / miR-193-5p / splicing factor SRSF10 / autophagy / atherogenesis

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Acknowledgements

This work was supported, in part, by the National Natural Science Foundation of China (Nos. 81773735, 81973313, and 81503069), the National Key R&D Program of China (No. 2017YFC1702003), the Natural Science Foundation of Heilongjiang Province (No. ZD2022H002) and the Fundamental Research Funds for the Provincial Universities-Academician Mr. Yu Weihan Foundation for Distinguished Young Scholars (No. JFYWH202001).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0931-4 and is accessible for authorized users.

Compliance with ethics guidelines

Yuhua Fan, Yue Zhang, Hongrui Zhao, Wenfeng Liu, Wanqing Xu, Lintong Jiang, Ranchen Xu, Yue Zheng, Xueqing Tang, Xiaohan Li, Limin Zhao, Xin Liu, Yang Hong, Yuan Lin, Hui Chen, and Yong Zhang declare that they have no conflicts of interest. This study was approved by the Institutional Animal Care and Use Committee of Harbin Medical University (Protocol (2009)-11) and conducted according to the Declaration of Helsinki and its amendments.

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