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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2023, Vol. 17 Issue (2) : 317-329    https://doi.org/10.1007/s11684-022-0931-4
RESEARCH ARTICLE
lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis
Yuhua Fan1,2, Yue Zhang1,3, Hongrui Zhao1, Wenfeng Liu1, Wanqing Xu1, Lintong Jiang1, Ranchen Xu1, Yue Zheng1, Xueqing Tang1, Xiaohan Li1, Limin Zhao1, Xin Liu1, Yang Hong1, Yuan Lin1, Hui Chen1, Yong Zhang1()
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 Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing 163319, China
3. Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
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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     
Corresponding Author(s): Yong Zhang   
Just Accepted Date: 11 November 2022   Online First Date: 13 January 2023    Issue Date: 26 May 2023
 Cite this article:   
Yuhua Fan,Yue Zhang,Hongrui Zhao, et al. lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis[J]. Front. Med., 2023, 17(2): 317-329.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0931-4
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I2/317
Primer name Sequences (5′–3′)
lncR-GAS5 Forward:5′-GTGTCCCCAAGGAAGGATGA-3′
Reverse:5′-ACCAGGAGCAGAACCATTAAGC-3′
CD31 Forward:5′-ACGCTGGTGCTCTATGCAAG-3′
Reverse:5′-TCAGTTGCTGCCCATTCATCA-3′
smMHC Forward:5′-AAGCTGCGGCTAGAGGTCA-3′
Reverse:5′-CCCTCCCTTTGATGGCTGAG-3′
IGF2 Forward:5′-GGGTGGGTAGAGCAATCAGG-3′
Reverse:5′-GGGCAAGTTCTTCCAATATGAC-3′
ACVR1 Forward:5′-TTCTGCTACGCCGTGGTC-3′
Reverse:5′-AAAGCCAAGGAAGGGAGG-3′
PRPS1 Forward:5′-CGTTGTTGATGCGAGAAA-3′
Reverse:5′-ATGGTGCTTGTGGGAGAT-3′
SRSF10 Forward:5′-TTCTGCTACGCCGTGGTC-3′
Reverse:5′-AAAGCCAAGGAAGGGAGG-3′
HOXA1 Forward:5′-AGGCTCTGGTGCTCCTGTCC-3′
Reverse:5′-CGCTCCCGCTGTTTACTC-3′
COL1A1 Forward:5′-AATCCATCGGTCATGCTCT-3′
Reverse:5′-TGCCATCAAAGTCTTCTGC-3′
MAP1LC3B Forward:5′-TTATAGAGCGATACAAGGGGGAG-3′
Reverse:5′-CGCCGTCTGATTATCTTGATGAG-3′
P62 Forward:5′-GACTGGCACCGCTACAACC-3′
Reverse:5′-CGTTGAAGGTGGCGAACTTCT-3′
GAPDH Forward:5′-AAGAAGGTGGTGAAGCAGGC-3′
Reverse:5′-TCCACCACCCAGTTGCTGTA-3′
miR-9 Forward:5′-CTAACGCTGCCGGAGATTAC-3′
Reverse:5′-TACTTGCCGCGCTTAAGATT-3′
miR-22 Forward:5′-CGGGCAGTTCTTCAGTGGCA-3′
Reverse:5′-CAGCCACAAAAGAGCACAAT-3′
miR-31 Forward:5′-CGGGCAGGCAAGATGCTGG-3′
Reverse:5′-CAGCCACAAAAGAGCACAAT-3′
miR-193-5p Forward:5′-CGGGCTGGGTCTTTGCGGGC-3′
Reverse:CAGCCACAAAAGAGCACAAT-3′
miR-222 Forward:5′-CGGGCCTCAGTAGCCAGTGT-3′
Reverse:5′-CAGCCACAAAAGAGCACAAT-3′
U6 Forward:5′-GCTTCGGCAGCACATATACTAAAAT-3′
Reverse:5′-CGCTTCACGAATTTGCGTGTCAT-3′
Tab.1  Sequences of primers showed as follows
Fig.1  LncR-GAS5 overexpression contributes to aggravating atherosclerosis. (A) Histological analysis of representative cross sections of the aortic root in ApoE−/− mice fed a high-fat diet (HFD) or chow diet (CD) for 12 weeks stained with hematoxylin and eosin (H&E, left) or Oil Red O (ORO, right). Scale bars, 400 μm. (B and C) Quantified H&E- or ORO-positive areas. (D) The collagen content is analyzed via Masson staining. Scale bars, 400 μm. (E) Quantitative analysis of collagen content. (F) ORO staining of representative en face aortas. (G) The quantified ORO-positive areas are analyzed. (H) Plaque area analysis is conducted by probing with CD68. Scale bars, 400 μm. (I) Quantification of the CD68-positive area. All data represent the mean ± SEM. *P < 0.05 or **P < 0.01 upon comparison with data from Lv null-infected ApoE−/− mice fed with HFD.
Fig.2  Autophagy is limited by lncR-GAS5. (A and B) LncR-GAS5 expression is analyzed in HAECs treated with ox-LDL (50 or 100 µg/mL) for 0, 1, 3, 6, or 24 h (n = 5 per group). (C) Transfection efficacy is confirmed through qRT-PCR (n = 5 per group). Western blot analysis of autophagy-related proteins (LC3 and p62) upon treatment with (D) lncR-GAS5 siRNA, (E) rapamycin (Rapa, 0, 30, 50, 100 nM), and (F) lncR-GAS5 plasmid (GAS5-P) (n = 5 per group). (G) Mean number of autolysosomes, represented by red puncta, and autophagosomes, represented by yellow puncta, per cell in merged images. The results are obtained by fluorescence microscopy (200×) (n = 5 per group). (H) Representative electronic micrographs and summarized data showing that the number of autophagic vacuoles is remarkably elevated in response to lncR-GAS5 knockdown. Images are shown at 20 000× magnification (n = 3 per group). All data represent the mean ± SEM. *P < 0.05 or **P < 0.01 vs. the control group or NC group; ##P < 0.01 vs. the NC-P plus rapamycin group.
Fig.3  LncR-GAS5 knockdown identifies the splicing factor SRSF10 as a crucial autophagy regulator. (A) QRT-PCR is performed to detect six dysregulated genes in the lncR-GAS5-knockdown group (n = 5 per group). (B and C) The mRNA level of SRSF10 is determined by incubating with ox-LDL (100 µg/mL) for 24 h and rapamycin (100 nM) for 4 h (n = 6 per group). (D and E) The protein expression of LC3/P62 and SRSF10 upon lncR-GAS5 knockdown or coincubation with SRSF10 plasmid is also determined (n = 3 per group). (F and G) The protein level of LC3/P62 and SRSF10 upon lncR-GAS5 plasmid or co-incubation with SRSF10 knockdown is also measured. “R” denotes rapamycin (n = 3 per group). (H) Immunofluorescence staining is performed to detect the expression of SRSF10 in the aortic sinus. The scale bars represent 100 µm (n = 3 per group). “L” denotes the lumen. The white arrow indicates SRSF10 in the endothelium. “+” indicates HFD feeding. (I) Mean number of autolysosomes, represented by red puncta, and autophagosomes, represented by yellow puncta, per cell in the merged images. The results are obtained by fluorescence microscopy (200×) (n = 5 per group). (J) Representative electronic micrographs showing that the number of autophagic vacuoles is elevated in response to SRSF10 knockdown. “N” indicates the nucleus; red arrow indicates autophagic vacuoles. Images are shown at 20 000× magnification (n = 3 per group). All data are presented as the mean ± SEM. *P < 0.05 or **P < 0.01 vs. the NC or control group; ##P < 0.01 vs. the si-GAS5 or GAS5-P + R group.
Fig.4  Experimental validation of SRSF10 as a target gene of miR-193-5p. (A) qRT-PCR analysis of si-GAS5-treated HAECs shows that miR-193-5p is significantly upregulated (n = 5 per group). **P < 0.01 vs. the NC group. (B) Sequence complementarity between miR-193-5p and the 3′-UTR of the splicing factor SRSF10. Red letters are matched bases. (C and D) Luciferase activity upon expression of the wild-type (wt) or mutant (mut) 3′-UTR of SRSF10 (n = 3 per group). **P < 0.01 vs. the NC mi (mimics) group. ##P < 0.01 vs. the NC inh (inhibitor) group. (E and F) Western blot is performed to detect the effect of lncR-GAS5 knockdown with or without the miR-193-5p inh (inhibitor) on LC3II/LC3I, SRSF10, and P62 protein levels (n = 3 per group). (G) Immunofluorescence staining verifies that miR-193-5p could decrease the protein level of SRSF10, but miR-193-5p inh promotes SRSF10 activation. The results are obtained through fluorescence microscopy (100×) (n = 5 per group). All data are presented as the mean ± SEM. *P < 0.05 or **P < 0.01 vs. NC or NC mi group. ##P < 0.01 vs. NC inh group.
Fig.5  miR-193-5p inhibition controls the occurrence of autophagy and limits autophagic flux in HAECs. (A and B) The relative miR-193-5p level is increased upon rapamycin incubation for 4 h; by contrast, ox-LDL (100 µg/mL) treatment for 24 h decreases miR-193-5p expression (n = 5 per group). (C) The miR-193-5p transfection efficiency is measured through qRT-PCR (n = 5 per group). (D) Representative images of fluorescent LC3 puncta after miR-193-5p transfection for 24 h. Mean number of autolysosomes, represented by red puncta, and autophagosomes, represented by yellow puncta, per cell in the merged images (n = 5 per group). The results are obtained by fluorescence microscopy (200×). (E) The LC3II/LC3I protein ratio and P62 protein express levels are measured (n = 3 per group). (F) TEM findings show that miR-193-5p overexpression elevated the number of autophagic vacuoles. The arrows indicate autophagosomes, and the nucleus is denoted by N. Images are shown at 20 000× magnification (n = 3 per group). All data are presented as the mean ± SEM. *P < 0.05 or **P < 0.01 vs. the control or NC mi group.
Fig.6  Forced expression of miR-193-5p arrests the development of atherosclerosis. (A) Histological analysis of representative cross-sections of the aortic roots in ApoE−/− mice fed with HFD for 12 weeks stained with H&E or ORO (left). The quantified H&E- or ORO-positive areas are shown (right). (B) En face aortas are analyzed through ORO staining. (C) Immunofluorescence staining is performed to determine the effect of miR-193-5p on the formation of plaques. (D) The collagen content is measured by Masson staining. The collagen content is shown in the right panel. Scale bars, 400 μm. “NC mi+” and “miR-193-5p mi+” indicate the NC mi + HFD and miR-193-5p mi + HFD groups, respectively. All data represent the mean ± SEM. *P < 0.05 or **P < 0.01 by comparison with data from the NC mi + group.
Fig.7  lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway.
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