Restoration of Autophagic Flux Improves Endothelial Function in Diabetes Through Lowering Mitochondrial ROS-mediated eNOS Monomerization

• DOI: 10.2337/figshare.19164119
• Publication Date: 2022-02-18T16:54:42Z
• Authors: Lei Zhao; Cheng-Lin Zhang; Lei He; Qinghua Chen; Limei Liu; Lijing Kang; Jian Liu; Jiang-Yun Luo; Lingshan Gou; Dan Qu; Wencong Song; Chi Wai Lau; Ho Ko; Vincent C.T. Mok; Xiao Yu Tian; Li Wang; Yu Huang
• Keywords: TFEB; Endothelial Dysfunction

<a>Endothelial nitric oxide synthase (eNOS) monomerization and uncoupling play crucial roles in mediating vascular dysfunction diabetes mellitus although the underlying mechanisms are still incompletely understood. Growing evidence indicates that autophagic dysregulation is involved pathogenesis of diabetic endothelial dysfunction, however, whether autophagy regulates eNOS activity through controlling monomerization/dimerization remains elusive. The present study shows flux was impaired endothelium <i>db/db</i> mice human cells exposed to advanced glycation end products or oxidized low-density lipoprotein. Inhibition by chloroquine bafilomycin A1 were sufficient induce lowers bioavailability raising mitochondrial reactive oxygen species (mtROS). Restoration overexpressing transcription factor EB (TFEB), a master regulator lysosomal biogenesis, decreased cell oxidative stress, increased dimerization improved endothelium-dependent relaxations (EDR) mouse aortas. mammalian target rapamycin kinase (mTOR) TFEB nuclear localization, reduced mtROS accumulation, facilitated dimerization, enhanced EDR mice. Moreover, calorie restriction also elevated expression, flux, restored aortas Taken together, reveals mtROS-induced closely associated with TFEB-autophagic axis leading mice.</a>