Comparative Transcription Profiling of MRNA and LncRNA in Pulmonary Arterial Hypertension After C75 Treatment

Overview

Journal BMC Pulm Med

Publisher Biomed Central

Specialty Pulmonary Medicine

Date 2023 Jan 31

PMID 36717804

Authors

Cuilan Hou

Lijian Xie

Tingxia Wang

Junmin Zheng

Yuqi Zhao

Qingzhu Qiu

Yi Yang

Tingting Xiao

Affiliations

Soon will be listed here.

Abstract

Objectives: To investigate mRNA and long non-coding RNA (lncRNA) expression profiles in monocrotaline (MCT)- mice.

Materials And Methods: Lung tissues (Control-Vehicle, MCT-Vehicle, and MCT-C75) were examined by high-throughput sequencing (HTS). Aberrantly expressed mRNAs and lncRNAs were analyzed by bioinformatics. Cell proliferation and cell cycle analysis were performed to detect the potential protective effects of C75, an inhibitor of fatty acid synthase. The signaling pathways associated with inflammatory responses were verified by real time-PCR.

Results: RNA sequencing data reveals 285 differentially expressed genes (DEGs) and 147 lncRNAs in the MCT-Vehicle group compared to the control. After five-week of C75 treatment, 514 DEGs and 84 lncRNAs are aberrant compared to the MCT-Vehicle group. Analysis of DEGs and lncRNA target genes reveals that they were enriched in pathways related to cell cycle, cell division, and vascular smooth muscle contraction that contributes to the PAH pathological process. Subsequently, the expression of eight DEGs and three lncRNAs is verified using RT-PCR. Differentially expressed lncRNAs (ENSMUSG00000110393.2, Gm38850, ENSMUSG00000100465.1, ENSMUSG00000110399.1) may associate in PAH pathogenesis as suggested by co-expression network analysis. C75 can protect against MCT-induced PAH through its anti-inflammatory and anti-proliferation.

Conclusions: These DEGs and lncRNAs can be considered as novel candidate regulators of PAH pathogenesis. We propose that C75 treatment can partially reverse PAH pathogenesis through modulating cell cycle, cell proliferation, and anti-inflammatory.

References

Dey B, Mueller A, Dutta A . Long non-coding RNAs as emerging regulators of differentiation, development, and disease. Transcription. 2014; 5(4):e944014. PMC: 4581346. DOI: 10.4161/21541272.2014.944014. View

Chen Y, Yuan T, Zhang H, Wang D, Yan Y, Niu Z . Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model. Acta Pharmacol Sin. 2016; 37(6):772-82. PMC: 4954764. DOI: 10.1038/aps.2016.22. View

Gabrielson E, Pinn M, Testa J, Kuhajda F . Increased fatty acid synthase is a therapeutic target in mesothelioma. Clin Cancer Res. 2001; 7(1):153-7. View

Xie X, Li S, Zhu Y, Liu L, Ke R, Wang J . Egr-1 mediates leptin-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells. Mol Biol Cell. 2017; 29(3):356-362. PMC: 5996952. DOI: 10.1091/mbc.E17-03-0141. View

Kaur G, Singh N, Samuel S, Bora H, Sharma S, Pachauri S . Withania somnifera shows a protective effect in monocrotaline-induced pulmonary hypertension. Pharm Biol. 2014; 53(1):147-57. DOI: 10.3109/13880209.2014.912240. View

Egan P, Liang O, Goldberg L, Aliotta J, Pereira M, Borgovan T . Low dose 100 cGy irradiation as a potential therapy for pulmonary hypertension. J Cell Physiol. 2019; 234(11):21193-21198. PMC: 6660348. DOI: 10.1002/jcp.28723. View

Coons J, Pogue K, Kolodziej A, Hirsch G, George M . Pulmonary Arterial Hypertension: a Pharmacotherapeutic Update. Curr Cardiol Rep. 2019; 21(11):141. DOI: 10.1007/s11886-019-1235-4. View

Jandl K, Thekkekara Puthenparampil H, Marsh L, Hoffmann J, Wilhelm J, Veith C . Long non-coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1-AS1. J Pathol. 2018; 247(3):357-370. PMC: 6900182. DOI: 10.1002/path.5195. View

Paulin R, Michelakis E . The metabolic theory of pulmonary arterial hypertension. Circ Res. 2014; 115(1):148-64. DOI: 10.1161/CIRCRESAHA.115.301130. View

10.

Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 1999; 28(1):27-30. PMC: 102409. DOI: 10.1093/nar/28.1.27. View

11.

Hou C, Chen J, Zhao Y, Niu Y, Lin S, Chen S . The Emerging Role of Fatty Acid Synthase in Hypoxia-Induced Pulmonary Hypertensive Mouse Energy Metabolism. Oxid Med Cell Longev. 2021; 2021:9990794. PMC: 8387195. DOI: 10.1155/2021/9990794. View

12.

Singh N, Manhas A, Kaur G, Jagavelu K, Hanif K . Inhibition of fatty acid synthase is protective in pulmonary hypertension. Br J Pharmacol. 2016; 173(12):2030-45. PMC: 4882492. DOI: 10.1111/bph.13495. View

13.

Hou C, Wang M, Sun C, Huang Y, Jin S, Mu X . Protective Effects of Hydrogen Sulfide in the Ageing Kidney. Oxid Med Cell Longev. 2016; 2016:7570489. PMC: 5108860. DOI: 10.1155/2016/7570489. View

14.

Ovet H, Oztay F . The copper chelator tetrathiomolybdate regressed bleomycin-induced pulmonary fibrosis in mice, by reducing lysyl oxidase expressions. Biol Trace Elem Res. 2014; 162(1-3):189-99. DOI: 10.1007/s12011-014-0142-1. View

15.

Mera P, Bentebibel A, Lopez-Vinas E, Cordente A, Gurunathan C, Sebastian D . C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem Pharmacol. 2008; 77(6):1084-95. DOI: 10.1016/j.bcp.2008.11.020. View

16.

Chen G, Zuo S, Tang J, Zuo C, Jia D, Liu Q . Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice. J Exp Med. 2018; 215(8):2175-2195. PMC: 6080901. DOI: 10.1084/jem.20171767. View

17.

Xiao T, Xie L, Huang M, Shen J . Differential expression of microRNA in the lungs of rats with pulmonary arterial hypertension. Mol Med Rep. 2016; 15(2):591-596. PMC: 5364860. DOI: 10.3892/mmr.2016.6043. View

18.

Bai Y, Li Z, Wang H, Lian G, Wang Y . The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB. Int J Mol Med. 2017; 40(1):155-163. PMC: 5466386. DOI: 10.3892/ijmm.2017.3001. View

19.

Bowen T, Adams V, Werner S, Fischer T, Vinke P, Brogger M . Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia. J Cachexia Sarcopenia Muscle. 2017; 8(6):939-953. PMC: 5700443. DOI: 10.1002/jcsm.12233. View

20.

Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M . KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2020; 49(D1):D545-D551. PMC: 7779016. DOI: 10.1093/nar/gkaa970. View