Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118(4): 620–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Poillet-Perez L, Xie X, Zhan L, Yang Y, Sharp DW, Hu ZS, Su X, Maganti A, Jiang C, Lu W, Zheng H, Bosenberg MW, Mehnert JM, Guo JY, Lattime E, Rabinowitz JD, White E. Autophagy maintains tumour growth through circulating arginine. Nature 2018; 563(7732): 569–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Torisu T, Torisu K, Lee IH, Liu J, Malide D, Combs CA, Wu XS, Rovira II II, Fergusson MM, Weigert R, Connelly PS, Daniels MP, Komatsu M, Cao L, Finkel T. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nat Med 2013; 19(10): 1281–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012; 11(9): 709–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vion AC, Kheloufi M, Hammoutene A, Poisson J, Lasselin J, Devue C, Pic I, Dupont N, Busse J, Stark K, Lafaurie-Janvore J, Barakat AI, Loyer X, Souyri M, Viollet B, Julia P, Tedgui A, Codogno P, Boulanger CM, Rautou PE. Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow. Proc Natl Acad Sci USA 2017; 114(41): E8675–E8684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pankratz F, Hohnloser C, Bemtgen X, Jaenich C, Kreuzaler S, Hoefer I, Pasterkamp G, Mastroianni J, Zeiser R, Smolka C, Schneider L, Martin J, Juschkat M, Helbing T, Moser M, Bode C, Grundmann S. MicroRNA-100 suppresses chronic vascular inflammation by stimulation of endothelial autophagy. Circ Res 2018; 122(3): 417–432

    Article  CAS  PubMed  Google Scholar 

  7. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell 2013; 154(1): 26–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu CY, Zhang YH, Li RB, Zhou LY, An T, Zhang RC, Zhai M, Huang Y, Yan KW, Dong YH, Ponnusamy M, Shan C, Xu S, Wang Q, Zhang YH, Zhang J, Wang K. LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat Commun 2018; 9(1): 29

    Article  PubMed  PubMed Central  Google Scholar 

  9. Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell 1988; 54(6): 787–793

    Article  CAS  PubMed  Google Scholar 

  10. Liang W, Fan T, Liu L, Zhang L. Knockdown of growth-arrest specific transcript 5 restores oxidized low-density lipoprotein-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells. Eur J Pharmacol 2019; 843: 154–161

    Article  CAS  PubMed  Google Scholar 

  11. Zhang N, Yang GQ, Shao XM, Wei L. GAS5 modulated autophagy is a mechanism modulating cisplatin sensitivity in NSCLC cells. Eur Rev Med Pharmacol Sci 2016; 20(11): 2271–2277

    CAS  PubMed  Google Scholar 

  12. Huo JF, Chen XB. Long noncoding RNA growth arrest-specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR-dependent manner. J Cell Biochem 2019; 120(4): 6127–6136

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Y, Qin W, Zhang L, Wu X, Du N, Hu Y, Li X, Shen N, Xiao D, Zhang H, Li Z, Zhang Y, Yang H, Gao F, Du Z, Xu C, Yang B. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis. Sci Rep 2015; 5(1): 9401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pan J, Alexan B, Dennis D, Bettina C, Christoph LIM, Tang Y. MicroRNA-193-3p attenuates myocardial injury of mice with sepsis via STAT3/HMGB1 axis. J Transl Med 2021; 19(1): 386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jiang C, Shen F, Du J, Fang X, Li X, Su J, Wang X, Huang X, Liu Z. Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression. Biomed Pharmacother 2018; 97: 844–850

    Article  CAS  PubMed  Google Scholar 

  16. Zheng X, Yu Q, Shang D, Yin C, Xie D, Huang T, Du X, Wang W, Yan X, Zhang C, Li W, Song Z. TAK1 accelerates transplant arteriosclerosis in rat aortic allografts by inducing autophagy in vascular smooth muscle cells. Atherosclerosis 2022; 343: 10–19

    Article  CAS  PubMed  Google Scholar 

  17. Fan Y, Liu L, Fang K, Huang T, Wan L, Liu Y, Zhang S, Yan D, Li G, Gao Y, Lv Y, Chen Y, Tu Y. Resveratrol ameliorates cardiac hypertrophy by down-regulation of miR-155 through activation of breast cancer type 1 susceptibility protein. J Am Heart Assoc 2016; 5(4): e002648

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jiang W, Zhao W, Ye F, Huang S, Wu Y, Chen H, Zhou R, Fu G. SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1. Atherosclerosis 2022; 340: 1–11

    Article  CAS  PubMed  Google Scholar 

  19. Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, Liu X, He S, Kraehling JR, Ulrich V, Lin CS, Velazquez H, Lasunción MA, Li G, Suárez Y, Tellides G, Swirski FK, Lee WL, Schwartz MA, Sessa WC, Fernández-Hernando C. Caveolin-1 regulates atherogenesis by attenuating low-density lipoprotein transcytosis and vascular inflammation independently of endothelial nitric oxide synthase activation. Circulation 2019; 140(3): 225–239

    Article  PubMed  PubMed Central  Google Scholar 

  20. Brauner S, Jiang X, Thorlacius GE, Lundberg AM, Östberg T, Yan ZQ, Kuchroo VK, Hansson GK, Wahren-Herlenius M. Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content. Cardiovasc Res 2018; 114(1): 158–167

    Article  CAS  PubMed  Google Scholar 

  21. Grootaert MOJ, Roth L, Schrijvers DM, De Meyer GRY, Martinet W. Defective autophagy in atherosclerosis: to die or to senesce? Oxid Med Cell Longev 2018; 2018: 7687083

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu KX, Chen GP, Lin PL, Huang JC, Lin X, Qi JC, Lin QC. Detection and analysis of apoptosis- and autophagy-related miRNAs of mouse vascular endothelial cells in chronic intermittent hypoxia model. Life Sci 2018; 193: 194–199

    Article  CAS  PubMed  Google Scholar 

  23. Chen L, Yang W, Guo Y, Chen W, Zheng P, Zeng J, Tong W. Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One 2017; 12(9): e0185406

    Article  PubMed  PubMed Central  Google Scholar 

  24. Meng XD, Yao HH, Wang LM, Yu M, Shi S, Yuan ZX, Liu J. Knockdown of GAS5 inhibits atherosclerosis progression via reducing EZH2-mediated ABCA1 transcription in ApoE−/− mice. Mol Ther Nucleic Acids 2020; 19: 84–96

    Article  CAS  PubMed  Google Scholar 

  25. Kheloufi M, Vion AC, Hammoutene A, Poisson J, Lasselin J, Devue C, Pic I, Dupont N, Busse J, Stark K, Lafaurie-Janvore J, Barakat AI, Loyer X, Souyri M, Viollet B, Julia P, Tedgui A, Codogno P, Boulanger CM, Rautou PE. Endothelial autophagic flux hampers atherosclerotic lesion development. Autophagy 2018; 14(1): 173–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liang W, Fan T, Liu L, Zhang L. Knockdown of growth-arrest specific transcript 5 restores oxidized low-density lipoprotein-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells. Eur J Pharmacol 2019; 843: 154–161

    Article  CAS  PubMed  Google Scholar 

  27. Feng Y, Chen M, Manley JL. Phosphorylation switches the general splicing repressor SRp38 to a sequence-specific activator. Nat Struct Mol Biol 2008; 15(10): 1040–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Torres-Odio S, Key J, Hoepken HH, Canet-Pons J, Valek L, Roller B, Walter M, Morales-Gordo B, Meierhofer D, Harter PN, Mittelbronn M, Tegeder I, Gispert S, Auburger G. Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation. J Neuroinflammation 2017; 14(1): 154

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  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

    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 & Yong Zhang

  2. Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319, China

    Yuhua Fan

  3. Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Yue Zhang

Authors
  1. Yuhua Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongrui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenfeng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wanqing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lintong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ranchen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yue Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xueqing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaohan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Limin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Zhang.

Ethics declarations

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.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, Y., Zhang, Y., Zhao, H. et al. lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis. Front. Med. 17, 317–329 (2023). https://doi.org/10.1007/s11684-022-0931-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-022-0931-4

Keywords

Search

Navigation