METTL3 mediates m6A methylation of ADAM17 to Downregulate ACE2–Ang-(1–7) axis and promote progression of hypertension

Introduction: Features of hypertension include imbalance between vascular relaxation and constriction along with vascular remodeling caused by endothelial dysfunction, further increasing peripheral resistance and blood pressure (BP). While N6-methyladenosine (m6A) modifications of RNA mediated by methyltransferase-like 3 (METTL3) regulates certain endothelial function, its roles and mechanisms in hypertension remain unknown. Objectives: This study was to examine roles of METTL3–m6A and its regulating targets on BP, cardiovascular function, and remodeling in hypertensive mice. Methods: We generated METTL3 conditional endothelial cell (EC) knockdown (EKD) mice as well as various EKD or EC overexpression (EOE) mice. We implanted mice with subcutaneous osmotic minipumps containing angiotensin II (Ang II) to induce hypertension and tested parameters of cardiovascular function and remodeling. Results: Compared to controls, METTL3 expression and m6A levels in arteries of both hypertensive patients and Ang II-treated mice were increased. METTL3-EKD decreased BP, vasoconstriction, and platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) plasma levels; improved cardiovascular remodeling and endothelium-dependent vasodilation; and augmented release of nitric oxide (NO) and endothelial NO synthase activity in hypertensive mice. m6A MeRIP-seq analysis showed that Ang II significantly upregulated m6A peaks of a disintegrin and metalloproteases 17 (ADAM17) RNA in mesenteric arteries, accompanied by increased ADAM17 and decreased angiotensin converting enzyme 2 (ACE2) expression and Ang-(1–7) plasma level, all of which were reversed by METTL3-EKD. ACE2-EKD abolished but ADAM17-EOE did not influence the effects of METTL3-EKD in hypertensive mice. We found similar results in cultured ECs, and nuclear export of ADAM17 RNA in ECs was elevated by Ang II, which again was reversed by METTL3-EKD. Conclusion: METTL3-EKD reduces BP and vasoconstriction and prevents cardiovascular remodeling by inhibiting the suppression of ADAM17 in ECs on the ACE2–Ang-(1–7) axis, and then improving Ang II-impaired endothelial function. This study may offer a novel prospective diagnostic or therapeutic strategy for hypertension.