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

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-a 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-a resulted in increased expression of miR-31 and VEC apoptosis. MiR-31 in-hibition strikingly decreased TNF-a and IL-17A co-induced VEC apoptosis. Mechanistically, in IL-17A and TNF-a co-stimulated VECs (co-induced VECs), we found that the activation of the NF-kB 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-a on VECs, trans-fection of siRNA E2F6 induced cell apoptosis without the stimulation of the above cytokines. In conclusion, TNF-a 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 sug-gests that the key factor between cytokine co-stimulation effect and VEC apoptosis was miR-31/E2F6 axis, which was mainly regulated by NF-KB signaling pathway. This gives us a new sight to treat hypertension-associated VR. (c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Vascular endothelial cell apoptosis is the fundamental cause of pulmonary arterial hypertension. MiR-31 is a novel target for hypertension treatment. This study aims to determine the role and mechanism of miR-31 in VEC apoptosis.