lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis.
10.1007/s11684-022-0931-4
- Author:
Yuhua FAN
1
;
Yue ZHANG
1
;
Hongrui ZHAO
1
;
Wenfeng LIU
1
;
Wanqing XU
1
;
Lintong JIANG
1
;
Ranchen XU
1
;
Yue ZHENG
1
;
Xueqing TANG
1
;
Xiaohan LI
1
;
Limin ZHAO
1
;
Xin LIU
1
;
Yang HONG
1
;
Yuan LIN
1
;
Hui CHEN
1
;
Yong ZHANG
2
Author Information
1. 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, 150081, China.
2. 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, 150081, China. hmuzhangyong@hotmail.com.
- Publication Type:Journal Article
- Keywords:
atherogenesis;
autophagy;
lncR-GAS5;
miR-193-5p;
splicing factor SRSF10
- MeSH:
Humans;
Atherosclerosis/genetics*;
Autophagy/genetics*;
Cell Cycle Proteins/metabolism*;
Endothelial Cells/metabolism*;
Endothelium/metabolism*;
MicroRNAs/metabolism*;
Repressor Proteins/metabolism*;
RNA Splicing Factors;
Serine-Arginine Splicing Factors/genetics*;
RNA, Long Noncoding/metabolism*
- From:
Frontiers of Medicine
2023;17(2):317-329
- CountryChina
- Language:English
-
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.
