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Int J Biol Sci 2020; 16(3):515-528. doi:10.7150/ijbs.34517 This issue Cite

Research Paper

Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia

Junming Fan*, Xiaofang Fan*, Hui Guang*, Xiaoqiong Shan, Qiuyun Tian, Fukun Zhang, Ran Chen, Fangzhou Ye, Hui Quan, Haizeng Zhang, Lu Ding, Zhuohui Gan, Feng Xue, Yongyu Wang, Sunzhong Mao, Lianggang Hu, Yongsheng Gong✉

Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
*These authors contributed equally to this work.

✉ Corresponding author: Yongsheng Gong, Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. E-mail: fxbwzmccom (YS Gong); Tel: (+86)577 86699521

Citation:
Fan J, Fan X, Guang H, Shan X, Tian Q, Zhang F, Chen R, Ye F, Quan H, Zhang H, Ding L, Gan Z, Xue F, Wang Y, Mao S, Hu L, Gong Y. Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia. Int J Biol Sci 2020; 16(3):515-528. doi:10.7150/ijbs.34517. https://www.ijbs.com/v16p0515.htm
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Abstract

Graphic abstract

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease that can lead to heart failure and eventually death. MicroRNAs (miRs) play essential roles during PAH progression; however, their exact mechanism of action remains unclear. Apelin is a small bioactive peptide with a key protective function in the pathogenesis of PAH mediated by binding to the APJ gene. The aim of the present study was to investigate the role of miR-335-3p in chronic normobaric hypoxia (CNH)-induced PAH in mice and the potential underlying regulatory mechanism. Adult male C57BL/6 mice were exposed to normoxia (~21% O2) or CNH (~10% O2, 23 h/d) for 5 weeks. MiR-335-3p was significantly increased in lung tissue of CNH-induced PAH mice. Blocking miR-335-3p attenuated CNH-induced PAH and alleviated pulmonary vascular remodeling. Bioinformatics analysis and luciferase reporter assay indicated that nuclear factor-kappa beta (NF-κB) acted as a transcriptional regulator upstream of miR-335-3p. Pyrrolidine dithiocarbamate treatment reversed the CNH-induced increase in miR-335-3p expression and diminished CNH-induced PAH. Moreover, p50-/- mice were resistant to CNH-induced PAH. Finally, APJ was identified as a direct targeting gene downstream of miR-335-3p, and pharmacological activation of APJ by its ligand apelin-13 reduced CNH-induced PAH and improved pulmonary vascular remodeling. Our results indicate that NF-κB-mediated transcriptional upregulation of miR-335-3p contributes to the inhibition of APJ and induction of PAH during hypoxia; hence, miR-335-3p could be a potential therapeutic target for hypoxic PAH.

Keywords: NF-κB, Pulmonary arterial hypertension, miR-335-3p, APJ, Hypoxia

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APA
Fan, J., Fan, X., Guang, H., Shan, X., Tian, Q., Zhang, F., Chen, R., Ye, F., Quan, H., Zhang, H., Ding, L., Gan, Z., Xue, F., Wang, Y., Mao, S., Hu, L., Gong, Y. (2020). Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia. International Journal of Biological Sciences, 16(3), 515-528. https://doi.org/10.7150/ijbs.34517.

ACS
Fan, J.; Fan, X.; Guang, H.; Shan, X.; Tian, Q.; Zhang, F.; Chen, R.; Ye, F.; Quan, H.; Zhang, H.; Ding, L.; Gan, Z.; Xue, F.; Wang, Y.; Mao, S.; Hu, L.; Gong, Y. Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia. Int. J. Biol. Sci. 2020, 16 (3), 515-528. DOI: 10.7150/ijbs.34517.

NLM
Fan J, Fan X, Guang H, Shan X, Tian Q, Zhang F, Chen R, Ye F, Quan H, Zhang H, Ding L, Gan Z, Xue F, Wang Y, Mao S, Hu L, Gong Y. Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia. Int J Biol Sci 2020; 16(3):515-528. doi:10.7150/ijbs.34517. https://www.ijbs.com/v16p0515.htm

CSE
Fan J, Fan X, Guang H, Shan X, Tian Q, Zhang F, Chen R, Ye F, Quan H, Zhang H, Ding L, Gan Z, Xue F, Wang Y, Mao S, Hu L, Gong Y. 2020. Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia. Int J Biol Sci. 16(3):515-528.

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