CBS 2019




Role of Low Endothelial Shear Stress and Plaque Characteristics in the Prediction of Nonculprit Major Adverse Cardiac Events: The PROSPECT Study Coronary Microcirculation in Ischemic Heart Disease Evolving understanding of the heterogeneous natural history of individual coronary artery plaques and the role of local endothelial shear stress Low Endothelial Shear Stress Predicts Evolution to High-Risk Coronary Plaque Phenotype in the Future: A Serial Optical Coherence Tomography and Computational Fluid Dynamics Study Local Low Shear Stress and Endothelial Dysfunction in Patients With Nonobstructive Coronary Atherosclerosis Angiographic derived endothelial shear stress: a new predictor of atherosclerotic disease progression Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION Study High Coronary Shear Stress in Patients With Coronary Artery Disease Predicts Myocardial Infarction Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway
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Original Research2018 May;1865(5):709-720.

JOURNAL:Biochim Biophys Acta. Article Link

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

Zhang JX, Qu XL, Chen SL et al. Keywords: Autophagic flux; Endothelial cells; Endothelial nitric oxide synthase uncoupling; Low shear stress


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 regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.