MicroRNA-31 regulates TNF-α and IL-17A co-induced-endothelial cell apoptosis by repressing E2F6

Zilong Fang; Xinran Tong; Guangzheng Shi; Wendong Chen; Qun Li

doi:10.1016/j.bbrc.2023.05.012

MicroRNA-31 regulates TNF-α and IL-17A co-induced-endothelial cell apoptosis by repressing E2F6

Biochem Biophys Res Commun. 2023 Jul 23:666:76-82. doi: 10.1016/j.bbrc.2023.05.012. Epub 2023 May 3.

Authors

Zilong Fang¹, Xinran Tong², Guangzheng Shi², Wendong Chen², Qun Li³

Affiliations

¹ Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China; The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.
² The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.
³ The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China. Electronic address: liqun@sibs.ac.cn.

PMID: 37178508
DOI: 10.1016/j.bbrc.2023.05.012

Abstract

Vascular endothelial cell (VEC) apoptosis is the fundamental cause of pulmonary arterial hypertension. MicroRNA-31 (MiR-31) is a novel target for hypertension treatment. However, the role and mechanism of miR-31 in the apoptosis of VECs remain unclear. The purpose of this study is to determine whether miR-31 plays an important role in VEC apoptosis as well as the detailed mechanisms involved. We found that pro-inflammatory cytokines IL-17A and TNF-α were highly expressed in serum and aorta, and the expression of miR-31 was significantly increased in aortic intimal tissue from Angiotensin II (AngII)- induced hypertensive mice (WT-AngII) compared with control mice (WT-NC). In vitro, co-stimulation of VECs with IL-17A and TNF-α resulted in increased expression of miR-31 and VEC apoptosis. MiR-31 inhibition strikingly decreased TNF-α and IL-17A co-induced VEC apoptosis. Mechanistically, in IL-17A and TNF-α co-stimulated VECs (co-induced VECs), we found that the activation of the NF-κB signal effectively increased the expression of miR-31. Dual-luciferase reporter gene assay revealed that miR-31 directly targeted and inhibited the expression of the E2F transcription factor 6 (E2F6). The expression of E2F6 was decreased in Co-induced VECs. MiR-31 inhibition significantly alleviated the decreased expression of E2F6 in co-induced VECs. Consistent with the co-stimulated effect of IL-17A and TNF-α on VECs, transfection of siRNA E2F6 induced cell apoptosis without the stimulation of the above cytokines. In conclusion, TNF-α and IL-17A generated in the aortic vascular tissue and serum from Ang II-induced hypertensive mice could trigger VECs apoptosis by the miR-31/E2F6 axis. To sum up, our study suggests that the key factor between cytokine co-stimulation effect and VEC apoptosis was miR-31/E2F6 axis, which was mainly regulated by NF-қB signaling pathway. This gives us a new sight to treat hypertension-associated VR.

Keywords: Apoptosis; E2F transcription Factor 6; Endothelial cell; MiR-31.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cytokines / metabolism
Endothelial Cells / metabolism
Hypertension* / metabolism
Interleukin-17 / metabolism
Interleukin-17 / pharmacology
Mice
MicroRNAs* / metabolism
NF-kappa B / metabolism
Tumor Necrosis Factor-alpha / metabolism

Substances

Cytokines
Interleukin-17
MicroRNAs
NF-kappa B
Tumor Necrosis Factor-alpha
Il17a protein, mouse
E2f6 protein, mouse
Mirn31 microRNA, mouse
Tnf protein, mouse