2. Academic Validation
  3. METTL3 mediates atheroprone flow-induced glycolysis in endothelial cells

METTL3 mediates atheroprone flow-induced glycolysis in endothelial cells

  • Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2424796122. doi: 10.1073/pnas.2424796122.
Guo-Jun Zhao # 1 2,  So Yun Han # 2,  Yajuan Li 3 4,  Dongqiang Yuan 5,  Shuo Qin 3,  Yuhan Li 3,  Hongje Jang 3,  Li-Jing Chen 4,  Tong-You Wade Wei 2,  Ming He 2,  Yi-Shun Li 3 4,  Zhen Bouman Chen 5,  Lingyan Shi 3,  Shu Chien 3 4,  John Y-J Shyy 2 4
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 2 Division of Cardiology, Department of Medicine, University of California, La Jolla, CA 92093.
  • 3 Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093.
  • 4 Institute of Engineering in Medicine, University of California, La Jolla, CA 92093.
  • 5 Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010.
  • # Contributed equally.
PMID: 40327688 DOI: 10.1073/pnas.2424796122
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 m6A methyltransferase for RNA N6-mehtyladenosine (m6A) modifications to regulate epitranscriptome and cellular functions. With the atheroprone flow upregulating METTL3 and m6A 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 m6A modifications of mRNAs encoding HK1, PFKFB3, and GCKR, which are rate-limiting Enzymes of glycolysis. These augmented m6A 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.

Keywords

atherosclerosis; endothelial cell; glycolysis; shear stress.

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