The potential role of long non-coding RNA Dnm3os in the activation of cardiac fibroblasts_Journal of Biomedical Engineering

Authors：

KONG Qihang ¹ , ZHOU Junteng ² , TIAN Geer ¹ , QUAN Yue ¹ , WU Wenchao ¹ ,  LIU Xiaojing ^1,2

1. Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;
2. Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

LIU Xiaojing, Email: liuxq@scu.edu.cn

Keywords：

long non-coding RNA Dnm3os; cardiac fibrosis; cardiac fibroblast activation; transforming growth factor-β1/Smad2/3

DOI：

10.7507/1001-5515.202102021

Video：

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Long non-coding RNA (lncRNA) Dnm3os plays a critical role in peritendinous fibrosis and pulmonary fibrosis, but its role in the process of cardiac fibrosis is still unclear. Therefore, we carried out study by using the myocardial fibrotic tissues obtained by thoracic aortic constriction (TAC) in an early study of our group, and the in vitro cardiac fibroblast activation model induced by transforming growth factor-β1 (TGF-β1). Quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and collagen gel contraction test were used to identify the changes of activation phenotype and the expression of Dnm3os in cardiac fibroblasts. Small interfering RNA was used to silence Dnm3os to explore its role in the activation of cardiac fibroblasts. The results showed that the expression of Dnm3os was increased significantly in myocardial fibrotic tissues and in the activated cardiac fibroblasts. And the activation of cardiac fibroblasts could be alleviated by Dnm3os silencing. Furthermore, the TGF-β1/Smad2/3 pathway was activated during the process of cardiac fibroblasts activation, while was inhibited after silencing Dnm3os. The results suggest that Dnm3os silencing may affect the process of cardiac fibroblast activation by inhibiting TGF-β1/Smad2/3 signal pathway. Therefore, interfering with the expression of lncRNA Dnm3os may be a potential target for the treatment of cardiac fibrosis.

Citation： KONG Qihang, ZHOU Junteng, TIAN Geer, QUAN Yue, WU Wenchao, LIU Xiaojing. The potential role of long non-coding RNA Dnm3os in the activation of cardiac fibroblasts. Journal of Biomedical Engineering, 2021, 38(3): 574-582. doi: 10.7507/1001-5515.202102021 Copy

1.	Perestrelo A R, Silva A C, Oliver-De L J, et al. Multiscale analysis of extracellular matrix remodeling in the failing heart. Circ Res, 2021, 128(1): 24-38.
2.	Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
3.	Morishige S, Takahashi-Yanaga F, Ishikane S, et al. 2, 5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation. Biochem Pharmacol, 2019, 168: 82-90.
4.	Gil N, Ulitsky I. Regulation of gene expression by cis-acting long non-coding RNAs. Nat Rev Genet, 2020, 21(2): 102-117.
5.	Qian X, Zhao J, Yeung P Y, et al. Revealing lncRNA structures and interactions by sequencing-based approaches. Trends Biochem Sci, 2019, 44(1): 33-52.
6.	Li Yongqin, Liang Yajun, Zhu Yujiao, et al. Noncoding RNAs in cardiac hypertrophy. J Cardiovasc Transl Res, 2018, 11(6): 439-449.
7.	Jusic A, Devaux Y. Action E U-C C mitochondrial noncoding RNA-regulatory network in cardiovascular disease. Basic Res Cardiol, 2020, 115: 23.
8.	LU Dongchao, Thum T. RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nat Rev Cardiol, 2019, 16(11): 661-674.
9.	Mei Z, Huang B, Zhang Y, et al. Histone deacetylase 6 negatively regulated microRNA-199a-5p induces the occurrence of preeclampsia by targeting VEGFA in vitro. Biomed Pharmacother, 2019, 114: 108805.
10.	Wang H. Ji X SMAD6, positively regulated by the DNM3OS-miR-134-5p axis, confers promoting effects to cell proliferation, migration and EMT process in retinoblastoma. Cancer Cell International, 2020, 2020(20): 23.
11.	Wang S, Ni B, Zhang Z, et al. Long non-coding RNA DNM3OS promotes tumor progression and EMT in gastric cancer by associating with Snail. Biochem Biophys Res Commun, 2019, 511(1): 57-62.
12.	Zheng W, Chen C, Chen S, et al. Integrated analysis of long non-coding RNAs and mRNAs associated with peritendinous fibrosis. J Adv Res, 2019, 15: 49-58.
13.	Savary G, Dewaeles E, Diazzi S, et al. The long noncoding RNA DNM3OS is a reservoir of fibromirs with major functions in lung fibroblast response to TGF-β and pulmonary fibrosis. Am J Respir Crit Care Med, 2019, 200(2): 184-198.
14.	Chen L, Chen R J, Kemper S, et al. Suppression of fibrogenic signaling in hepatic stellate cells by twist1-dependent microRNA-214 expression: role of exosomes in horizontal transfer of twist1. Am J Physiol Gastrointest Liver Physiol, 2015, 309(6): G491-G499.
15.	Zhou J, Tian G, Quan Y, et al. Inhibition of P2X7 purinergic receptor ameliorates cardiac fibrosis by suppressing NLRP3/IL-1beta pathway. Oxid Med Cell Longev, 2020, 2020: 7956274.
16.	Lee S A, Yang H W, Um J Y, et al. Vitamin D attenuates myofibroblast differentiation and extracellular matrix accumulation in nasal polyp-derived fibroblasts through smad2/3 signaling pathway. Sci Rep, 2017, 7: 7299.
17.	Qu J, Li M, Li D, et al. Stimulation of sigma-1 receptor protects against cardiac fibrosis by alleviating IRE1 pathway and autophagy impairment. Oxid Med Cell Longev, 2021, 2021: 8836818.
18.	Ramjee V, Li D, Manderfield L J, et al. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J Clin Invest, 2017, 127(3): 899-911.
19.	Zhao Y, Wang C, Hong X, et al. Wnt/β-catenin signaling mediates both heart and kidney injury in type 2 cardiorenal syndrome. Kidney Int, 2019, 95(4): 815-829.
20.	Yao Y, Hu C, Song Q, et al. ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart. Cardiovasc Res, 2020, 116(5): 956-969.
21.	Oatmen K E, Cull E, Spinale F G. Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype. Nat Rev Cardiol, 2020, 17(8): 523-531.
22.	Greco S, Salgado S A, Devaux Y, et al. Long noncoding RNAs and cardiac disease. Antioxid Redox Signal, 2018, 29(9): 880-901.
23.	Lozano-Vidal N, Bink D I, Boon R A. Long noncoding RNA in cardiac aging and disease. J Mol Cell Biol, 2019, 11(10): 860-867.
24.	Piccoli M T, Gupta S K, Viereck J, et al. Inhibition of the cardiac fibroblast-enriched lncRNA meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res, 2017, 121(5): 575-583.
25.	Liang H, Pan Z, Zhao X, et al. LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d. Theranostics, 2018, 8(4): 1180-1194.
26.	Zhang F, Fu X, Kataoka M, et al. Long noncoding RNA Cfast regulates cardiac fibrosis. Mol Ther Nucleic Acids, 2021, 23: 377-392.
27.	Das S, Reddy M, Senapati P, et al. Diabetes Mellitus-Induced long noncoding RNA Dnm3os regulates macrophage functions and inflammation via nuclear mechanisms. Arterioscler Thromb Vasc Biol, 2018, 38(8): 1806-1820.
28.	el Azzouzi H, Leptidis S, Dirkx E, et al. The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab, 2013, 18(3): 341-354.
29.	Higgins S P, Tang Y, Higgins C E, et al. TGF-β1/p53 signaling in renal fibrogenesis. Cell Signal, 2018, 43: 1-10.
30.	Wu C, Chen W, Ding H, et al. Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3at linker regions in vivo and in vitro. Life Sciences, 2019, 239: 116881.
31.	Lv Q, Wang J, Xu C, et al. Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3beta/beta-catenin and TGF-beta1/Smad2/3 signaling pathways. Mol Med, 2020, 26: 49.
32.	Arno B, Galli F, Roostalu U, et al. TNAP limits TGF-beta-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors. J Cell Sci, 2019.
33.	Zhu J X, Ling W, Xue C, et al. Higenamine attenuates cardiac fibroblast activation and fibrosis via inhibition of TGF-beta1/Smad signaling. European Journal of Pharmacology, 2021: 174013.

1. Perestrelo A R, Silva A C, Oliver-De L J, et al. Multiscale analysis of extracellular matrix remodeling in the failing heart. Circ Res, 2021, 128(1): 24-38.
2. Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
3. Morishige S, Takahashi-Yanaga F, Ishikane S, et al. 2, 5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation. Biochem Pharmacol, 2019, 168: 82-90.
4. Gil N, Ulitsky I. Regulation of gene expression by cis-acting long non-coding RNAs. Nat Rev Genet, 2020, 21(2): 102-117.
5. Qian X, Zhao J, Yeung P Y, et al. Revealing lncRNA structures and interactions by sequencing-based approaches. Trends Biochem Sci, 2019, 44(1): 33-52.
6. Li Yongqin, Liang Yajun, Zhu Yujiao, et al. Noncoding RNAs in cardiac hypertrophy. J Cardiovasc Transl Res, 2018, 11(6): 439-449.
7. Jusic A, Devaux Y. Action E U-C C mitochondrial noncoding RNA-regulatory network in cardiovascular disease. Basic Res Cardiol, 2020, 115: 23.
8. LU Dongchao, Thum T. RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nat Rev Cardiol, 2019, 16(11): 661-674.
9. Mei Z, Huang B, Zhang Y, et al. Histone deacetylase 6 negatively regulated microRNA-199a-5p induces the occurrence of preeclampsia by targeting VEGFA in vitro. Biomed Pharmacother, 2019, 114: 108805.
10. Wang H. Ji X SMAD6, positively regulated by the DNM3OS-miR-134-5p axis, confers promoting effects to cell proliferation, migration and EMT process in retinoblastoma. Cancer Cell International, 2020, 2020(20): 23.
11. Wang S, Ni B, Zhang Z, et al. Long non-coding RNA DNM3OS promotes tumor progression and EMT in gastric cancer by associating with Snail. Biochem Biophys Res Commun, 2019, 511(1): 57-62.
12. Zheng W, Chen C, Chen S, et al. Integrated analysis of long non-coding RNAs and mRNAs associated with peritendinous fibrosis. J Adv Res, 2019, 15: 49-58.
13. Savary G, Dewaeles E, Diazzi S, et al. The long noncoding RNA DNM3OS is a reservoir of fibromirs with major functions in lung fibroblast response to TGF-β and pulmonary fibrosis. Am J Respir Crit Care Med, 2019, 200(2): 184-198.
14. Chen L, Chen R J, Kemper S, et al. Suppression of fibrogenic signaling in hepatic stellate cells by twist1-dependent microRNA-214 expression: role of exosomes in horizontal transfer of twist1. Am J Physiol Gastrointest Liver Physiol, 2015, 309(6): G491-G499.
15. Zhou J, Tian G, Quan Y, et al. Inhibition of P2X7 purinergic receptor ameliorates cardiac fibrosis by suppressing NLRP3/IL-1beta pathway. Oxid Med Cell Longev, 2020, 2020: 7956274.
16. Lee S A, Yang H W, Um J Y, et al. Vitamin D attenuates myofibroblast differentiation and extracellular matrix accumulation in nasal polyp-derived fibroblasts through smad2/3 signaling pathway. Sci Rep, 2017, 7: 7299.
17. Qu J, Li M, Li D, et al. Stimulation of sigma-1 receptor protects against cardiac fibrosis by alleviating IRE1 pathway and autophagy impairment. Oxid Med Cell Longev, 2021, 2021: 8836818.
18. Ramjee V, Li D, Manderfield L J, et al. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J Clin Invest, 2017, 127(3): 899-911.
19. Zhao Y, Wang C, Hong X, et al. Wnt/β-catenin signaling mediates both heart and kidney injury in type 2 cardiorenal syndrome. Kidney Int, 2019, 95(4): 815-829.
20. Yao Y, Hu C, Song Q, et al. ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart. Cardiovasc Res, 2020, 116(5): 956-969.
21. Oatmen K E, Cull E, Spinale F G. Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype. Nat Rev Cardiol, 2020, 17(8): 523-531.
22. Greco S, Salgado S A, Devaux Y, et al. Long noncoding RNAs and cardiac disease. Antioxid Redox Signal, 2018, 29(9): 880-901.
23. Lozano-Vidal N, Bink D I, Boon R A. Long noncoding RNA in cardiac aging and disease. J Mol Cell Biol, 2019, 11(10): 860-867.
24. Piccoli M T, Gupta S K, Viereck J, et al. Inhibition of the cardiac fibroblast-enriched lncRNA meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res, 2017, 121(5): 575-583.
25. Liang H, Pan Z, Zhao X, et al. LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d. Theranostics, 2018, 8(4): 1180-1194.
26. Zhang F, Fu X, Kataoka M, et al. Long noncoding RNA Cfast regulates cardiac fibrosis. Mol Ther Nucleic Acids, 2021, 23: 377-392.
27. Das S, Reddy M, Senapati P, et al. Diabetes Mellitus-Induced long noncoding RNA Dnm3os regulates macrophage functions and inflammation via nuclear mechanisms. Arterioscler Thromb Vasc Biol, 2018, 38(8): 1806-1820.
28. el Azzouzi H, Leptidis S, Dirkx E, et al. The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab, 2013, 18(3): 341-354.
29. Higgins S P, Tang Y, Higgins C E, et al. TGF-β1/p53 signaling in renal fibrogenesis. Cell Signal, 2018, 43: 1-10.
30. Wu C, Chen W, Ding H, et al. Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3at linker regions in vivo and in vitro. Life Sciences, 2019, 239: 116881.
31. Lv Q, Wang J, Xu C, et al. Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3beta/beta-catenin and TGF-beta1/Smad2/3 signaling pathways. Mol Med, 2020, 26: 49.
32. Arno B, Galli F, Roostalu U, et al. TNAP limits TGF-beta-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors. J Cell Sci, 2019.
33. Zhu J X, Ling W, Xue C, et al. Higenamine attenuates cardiac fibroblast activation and fibrosis via inhibition of TGF-beta1/Smad signaling. European Journal of Pharmacology, 2021: 174013.

Journal of Biomedical Engineering

The potential role of long non-coding RNA Dnm3os in the activation of cardiac fibroblasts

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