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Respiratory Research
Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Pulmonary Hypertension | Research

CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis

Authors: Yuanyuan Sun, Rong Jiang, Xiaoyi Hu, Sugang Gong, Lan Wang, Wenhui Wu, Jinling Li, Xinyang Kang, Shijin Xia, Jinming Liu, Qinhua Zhao, Ping Yuan

Published in: Respiratory Research | Issue 1/2022

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Abstract

Background

Our previous study showed that circular RNA-gamma-secretase-activating protein (circGSAP) was down-regulated in pulmonary microvascular endothelial cells (PMECs) in response to hypoxia, and regulated the cell cycle of PMECs via miR-942-5p sponge in pulmonary hypertension (PH). However, the mechanism whether circGSAP affects the dysfunction of PEMCs through other microRNAs (miRNAs) remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of circGSAP regulating PMECs dysfunction by absorbing other miRNAs to regulate target genes in idiopathic pulmonary arterial hypertension (IPAH).

Methods

Quantitative real-time polymerase chain reaction, immunofluorescence staining, Cell Counting Kit-8, Calcein-AM/PI staining, Transwell assay, dual-luciferase reporter assay, and ELISA were used to elucidate the roles of circGSAP.

Results

Here we showed that plasma circGSAP levels were significantly decreased in patients with IPAH and associated with poor outcomes. In vivo, circGSAP overexpression improved survival, and alleviated pulmonary vascular remodeling of monocrotaline-induced PH (MCT-PH) rats. In vitro, circGSAP overexpression inhibited hypoxia-induced PMECs proliferation, migration and increased mortality by absorbing miR-27a-3p. BMPR2 was identified as a miR-27a-3p target gene. BMPR2 silencing ameliorated the effect of the miR-27a-3p inhibitor on PMECs proliferation,migration and mortality. The levels of BMPR2 were upregulated in circGSAP-overexpressed PMECs and lung tissues of MCT-PH rats.

Conclusion

Our findings demonstrated that circGSAP alleviated the dysfunction of PMECs via the increase of BMPR2 by competitively binding with miR-27a-3p, and mitigated pulmonary vascular remodeling of MCT-PH rats, providing potential therapeutic strategies for IPAH.
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Literature
1.
Scott TE, Qin CX, Drummond GR, Hobbs AJ, Kemp-Harper BK. Innovative anti-inflammatory and pro-resolving strategies for pulmonary hypertension: high blood pressure Research Council of Australia Award 2019. Hypertension. 2021;78:1168–84.CrossRefPubMed
2.
Nickel NP, Yuan K, Dorfmuller P, Provencher S, Lai YC, Bonnet S, Austin ED, Koch CD, Morris A, Perros F, et al. Beyond the lungs: systemic manifestations of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2020;201:148–57.CrossRefPubMedPubMedCentral
3.
Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.CrossRefPubMedPubMedCentral
4.
Zehendner CM, Valasarajan C, Werner A, Boeckel JN, Bischoff FC, John D, Weirick T, Glaser SF, Rossbach O, Jae N, et al. Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRbeta. Am J Respir Crit Care Med. 2020;202:1445–57.CrossRefPubMedPubMedCentral
5.
Nicolls MR, Voelkel NF. The roles of immunity in the prevention and evolution of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2017;195:1292–9.CrossRefPubMedPubMedCentral
6.
Zhou S, Jiang H, Li M, Wu P, Sun L, Liu Y, Zhu K, Zhang B, Sun G, Cao C, Wang R. Circular RNA hsa_circ_0016070 is associated with pulmonary arterial hypertension by promoting PASMC proliferation. Mol Ther Nucleic Acids. 2019;18:275–84.CrossRefPubMedPubMedCentral
7.
Zhang J, Li Y, Qi J, Yu X, Ren H, Zhao X, Xin W, He S, Zheng X, Ma C, et al. Circ-calm4 serves as an mir-337-3p sponge to regulate Myo10 (myosin 10) and promote pulmonary artery smooth muscle proliferation. Hypertension. 2020;75:668–79.CrossRefPubMed
8.
Wang Q, Sun Y, Zhao Q, Wu W, Wang L, Miao Y, Yuan P. Circular RNAs in pulmonary hypertension: emerging biological concepts and potential mechanism. Anim Model Exp Med. 2022;5:38–47.CrossRef
9.
Pullamsetti SS, Mamazhakypov A, Weissmann N, Seeger W, Savai R. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest. 2020;130:5638–51.CrossRefPubMedPubMedCentral
10.
Yuan P, Wu WH, Gong SG, Jiang R, Zhao QH, Pudasaini B, Sun YY, Li JL, Liu JM, Wang L. Impact of circGSAP in peripheral blood mononuclear cells on idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2021;203:1579–83.CrossRefPubMed
11.
Sun Y, Wu W, Zhao Q, Jiang R, Li J, Wang L, Xia S, Liu M, Gong S, Liu J, Yuan P. CircGSAP regulates the cell cycle of pulmonary microvascular endothelial cells via the mir-942-5p sponge in pulmonary hypertension. Front Cell Dev Biol. 2022; 10:967708.CrossRefPubMedPubMedCentral
12.
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the european respiratory society (ERS): endorsed by: Association for European Paediatric and congenital cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.CrossRefPubMed
13.
Sun Y, Wu W, Zhao Q, Jiang R, Li J, Wang L, Xia S, Liu M, Gong S, Liu J, Yuan P. CircGSAP regulates the cell cycle of pulmonary microvascular endothelial cells via the mir-942-5p sponge in pulmonary hypertension. Front Cell Dev Biol. 2022;10:967708.CrossRefPubMedPubMedCentral
14.
Ma C, Gu R, Wang X, He S, Bai J, Zhang L, Zhang J, Li Q, Qu L, Xin W, et al. circRNA CDR1as promotes pulmonary artery smooth muscle cell calcification by upregulating CAMK2D and CNN3 via sponging miR-7-5p. Mol Ther Nucleic Acids. 2020;22:530–41.CrossRefPubMedPubMedCentral
15.
Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, Luo Y, Lyu D, Li Y, Shi G, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016;7:11215.CrossRefPubMedPubMedCentral
16.
Yang L, Liang H, Meng X, Shen L, Guan Z, Hei B, Yu H, Qi S, Wen X. mmu_circ_0000790 is involved in pulmonary vascular remodeling in mice with HPH via MicroRNA-374c-mediated FOXC1. Mol Ther Nucleic Acids. 2020;20:292–307.CrossRefPubMedPubMedCentral
17.
Jiang Y, Liu H, Yu H, Zhou Y, Zhang J, Xin W, Li Y, He S, Ma C, Zheng X, et al. Circular RNA Calm4 regulates hypoxia-induced pulmonary arterial smooth muscle cells pyroptosis via the Circ-Calm4/miR-124-3p/PDCD6 Axis. Arterioscler Thromb Vasc Biol. 2021;41:1675–93.CrossRefPubMedPubMedCentral
18.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.CrossRefPubMed
19.
Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.CrossRefPubMed
20.
21.
Sun YY, Wang L, Liu JM, Yuan P, Reply to Sun, et al. circGASP: a new clinical biomarker for idiopathic pulmonary hypertension? Am J Respir Crit Care Med. 2022;205:254.CrossRefPubMed
22.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.CrossRefPubMed
23.
Sun Y, Wang Q, Zhang Y, Geng M, Wei Y, Liu Y, Liu S, Petersen RB, Yue J, Huang K, Zheng L. Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p. J Hepatol. 2020;73:603–15.CrossRefPubMed
24.
Castano C, Kalko S, Novials A, Parrizas M. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci U S A. 2018;115:12158–63.CrossRefPubMedPubMedCentral
25.
Morquette B, Juzwik CA, Drake SS, Charabati M, Zhang Y, Lecuyer MA, Galloway DA, Dumas A, de Faria Junior O, Paradis-Isler N, et al. MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis. Brain. 2019;142:2979–95.CrossRefPubMed
26.
Zahedi F, Nazari-Jahantigh M, Zhou Z, Subramanian P, Wei Y, Grommes J, Offermanns S, Steffens S, Weber C, Schober A. Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair. Cell Mol Life Sci. 2017;74:359–72.CrossRefPubMed
27.
Choe N, Kwon DH, Ryu J, Shin S, Cho HJ, Joung H, Eom GH, Ahn Y, Park WJ, Nam KI, et al. miR-27a-3p targets ATF3 to reduce calcium deposition in vascular smooth muscle cells. Mol Ther Nucleic Acids. 2020;22:627–39.CrossRefPubMedPubMedCentral
28.
Liu D, Liu QQ, Eyries M, Wu WH, Yuan P, Zhang R, Soubrier F, Jing ZC. Molecular genetics and clinical features of chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J. 2012;39:597–603.CrossRefPubMed
29.
Liu D, Morrell NW. Genetics and the molecular pathogenesis of pulmonary arterial hypertension. Curr Hypertens Rep. 2013;15:632–7.CrossRefPubMed
30.
Hennigs JK, Cao A, Li CG, Shi M, Mienert J, Miyagawa K, Korbelin J, Marciano DP, Chen PI, Roughley M, et al. PPARgamma-p53-mediated vasculoregenerative program to reverse pulmonary hypertension. Circ Res. 2021;128:401–18.CrossRefPubMed
31.
Du M, Jiang H, Liu H, Zhao X, Zhou Y, Zhou F, Piao C, Xu G, Ma F, Wang J, et al. Single-cell RNA sequencing reveals that BMPR2 mutation regulates right ventricular function via ID genes. Eur Respir J. 2021;60:2100327.CrossRef
32.
Hautefort A, Mendes-Ferreira P, Sabourin J, Manaud G, Bertero T, Rucker-Martin C, Riou M, Adao R, Manoury B, Lambert M, et al. Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension. Circulation. 2019;139:932–48.CrossRefPubMed
33.
Miyagawa K, Shi M, Chen PI, Hennigs JK, Zhao Z, Wang M, Li CG, Saito T, Taylor S, Sa S, et al. Smooth muscle contact drives endothelial regeneration by BMPR2-Notch1-mediated metabolic and epigenetic changes. Circ Res. 2019;124:211–24.CrossRefPubMedPubMedCentral
34.
Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, Gassmann M, Ostergaard L, Gay S, Speich R, Huber LC. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J. 2014;35:3203–11.CrossRefPubMed
35.
Shi W, Wang Q, Wang J, Yan X, Feng W, Zhang Q, Zhai C, Chai L, Li S, Xie X, Li M. Activation of yes-associated protein mediates sphingosine-1-phosphate-induced proliferation and migration of pulmonary artery smooth muscle cells and its potential mechanisms. J Cell Physiol. 2021;236:4694–708.CrossRefPubMed
Metadata
Title
CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis
Authors
Yuanyuan Sun
Rong Jiang
Xiaoyi Hu
Sugang Gong
Lan Wang
Wenhui Wu
Jinling Li
Xinyang Kang
Shijin Xia
Jinming Liu
Qinhua Zhao
Ping Yuan
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-02248-7

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