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bioRxiv · 10.1101/2023.12.11.571191

Regulation of blood pressure by METTL3 via RUNX1b-eNOS pathway in endothelial cells

Li, B.·Zhang, Y.·Yang, X.·Lan, M.·Yuan, Z.·Li, S.·Liu, Y.·Han, C.·Ai, D.·Yang, Y.·Zhu, Y.
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Abstract

BackgroundEndothelial cells regulate vascular tone to control the blood pressure (BP) by producing both relaxing and contracting factors. Previously, we identified methyltransferase-like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, as a key player in alleviating endothelial atherogenic progression. However, its involvement in BP regulation remains unclear. MethodsTo evaluate the role of METTL3 in vivo, mice with EC specific METTL3 deficiency (EC-Mettl3KO) with or without Ang II infusion were used to create a hypertensive model. Functional and MeRIP sequencing analysis were performed to explore the mechanism of METTL3-mediated hypertension. ResultsWe observed a reduction in endothelial METTL3 activity by Ang II in vitro and in vivo. Endothelial METTL3-deficient mice exhibited higher BP than controls, both before and after Ang II infusion. Through m6A sequencing and functional analysis, we identified m6A modification of various RUNX1 monomers resulted in endothelial dysfunction. Mutations in the 3'UTR region of RUNX1b abolished its luciferase reporter activity, and enhanced eNOS promoter luciferase reporter activity with or without METTL3 overexpression. Overexpression of METTL3 by adeno-associated virus reduced Ang II-induced BP elevation. ConclusionThis study reveals that METTL3 alleviates hypertension through m6A-dependent stabilization of RUNX1b mRNA, leading to upregulation of eNOS, thus underscoring the pivotal role of RNA transcriptomics in the regulation of hypertension.

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Li, B., Zhang, Y., Yang, X., Lan, M., Yuan, Z., Li, S., Liu, Y., Han, C., Ai, D., Yang, Y., Zhu, Y.. 2023-12-12. Regulation of blood pressure by METTL3 via RUNX1b-eNOS pathway in endothelial cells. https://doi.org/10.1101/2023.12.11.571191

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