METTL3 mediates atheroprone flow–induced glycolysis in endothelial cells

Abstract

Atheroprone flow–increased glycolysis in vascular endothelial cells (ECs) is pivotal in EC dysfunction and the initiation of atherosclerosis. Methyltransferase 3 (METTL3) is a major m 6 A methyltransferase for RNA N6-mehtyladenosine (m 6 A) modifications to regulate epitranscriptome and cellular functions. With the atheroprone flow upregulating METTL3 and m 6 A RNA hypermethylation, we investigate the role of METTL3 in atheroprone flow–induced glycolysis in ECs in vitro and in vivo. Compared to pulsatile shear stress (PS, atheroprotective flow), oscillatory shear stress (OS, atheroprone flow) increases METTL3 expression to enhance the m 6 A modifications of mRNAs encoding HK1, PFKFB3, and GCKR, which are rate-limiting enzymes of glycolysis. These augmented m 6 A modifications increase the expressions of HK1 and PFKFB3 while decreasing GCKR, resulting in elevated EC glycolysis, as revealed by seahorse analysis. Moreover, a stimulated Raman scattering (SRS) imaging study demonstrates the elevation of glucose incorporation into de novo synthesized lipids in ECs under atheroprone flow in vitro and in vivo. Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i) drug, represses METTL3 expression, thereby mitigating OS-induced glycolysis in ECs. These data suggest mechanisms by which METTL3 links EC mechanotransduction with metabolic reprogramming under atherogenic conditions.