Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation

Biochimica Et Biophysica Acta. Molecular Cell Research
Jun-Xia ZhangShao-Liang Chen

Abstract

Uncoupled endothelial nitric oxide synthase (eNOS) produces O2- instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O2- production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O2- burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O2- releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regu...Continue Reading

Citations

Apr 16, 2019·American Journal of Hypertension·Cameron G McCarthyBina Joe
Aug 31, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Cameron G McCarthyR Clinton Webb
Jan 28, 2020·Expert Opinion on Therapeutic Targets·Dorien G De MunckWim Martinet
Jun 14, 2020·American Journal of Hypertension·Zachary J SchreckenbergerCameron G McCarthy
Jun 9, 2020·Basic Research in Cardiology·William E HughesDavid D Gutterman
Jun 5, 2020·Journal of Cardiovascular Translational Research·Guoliang HeWeijian Wang
Nov 25, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·William E HughesDavid D Gutterman
Apr 4, 2021·Cells·James M HendersonDonato Santovito
May 7, 2021·Cardiovascular Research·Damián GaticaDaniel J Klionsky
Sep 3, 2021·Journal of Cell Science·Aurore Claude-TaupinNicolas Dupont
Sep 10, 2021·JCI Insight·Cameron G McCarthyBina Joe
Nov 9, 2021·Biochemical Society Transactions·Etienne MorelPatrice Codogno

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