Zhao Guo-Jun, Han So Yun, Li Yajuan, Yuan Dongqiang, Qin Shuo, Li Yuhan, Jang Hongje, Chen Li-Jing, Wei Tong-You Wade, He Ming, Li Yi-Shun, Bouman Chen Zhen, Shi Lingyan, Chien Shu, Shyy John Y-J
Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Division of Cardiology, Department of Medicine, University of California, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2424796122. doi: 10.1073/pnas.2424796122. Epub 2025 May 6.
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 mA methyltransferase for RNA N6-mehtyladenosine (mA) modifications to regulate epitranscriptome and cellular functions. With the atheroprone flow upregulating METTL3 and mA 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 mA modifications of mRNAs encoding HK1, PFKFB3, and GCKR, which are rate-limiting enzymes of glycolysis. These augmented mA 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.
促动脉粥样硬化血流增加血管内皮细胞（ECs）中的糖酵解，这在EC功能障碍和动脉粥样硬化的起始中起关键作用。甲基转移酶3（METTL3）是一种主要的RNA N6-甲基腺苷（m⁶A）修饰的甲基转移酶，用于调节表观转录组和细胞功能。随着促动脉粥样硬化血流上调METTL3和m⁶A RNA高甲基化，我们在体外和体内研究了METTL3在促动脉粥样硬化血流诱导的ECs糖酵解中的作用。与搏动性剪切应力（PS，抗动脉粥样硬化血流）相比，振荡性剪切应力（OS，促动脉粥样硬化血流）增加METTL3表达，以增强编码HK1、PFKFB3和GCKR的mRNA的m⁶A修饰，这些是糖酵解的限速酶。如海马分析所示，这些增加的m⁶A修饰增加了HK1和PFKFB3的表达，同时降低了GCKR，导致EC糖酵解升高。此外，受激拉曼散射（SRS）成像研究表明，在体外和体内促动脉粥样硬化血流条件下，ECs中葡萄糖掺入新合成脂质的水平升高。恩格列净，一种钠-葡萄糖协同转运蛋白-2抑制剂（SGLT2i）药物，可抑制METTL3表达，从而减轻OS诱导的ECs糖酵解。这些数据表明了METTL3在动脉粥样硬化条件下将EC机械转导与代谢重编程联系起来的机制。
