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Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION Study Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway High Coronary Shear Stress in Patients With Coronary Artery Disease Predicts Myocardial Infarction Evolving insights into the role of local shear stress in late stent failure from neoatherosclerosis formation and plaque destabilization Role of local coronary blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and coronary plaque Implications of the local hemodynamic forces on the formation and destabilization of neoatherosclerotic lesions Role of endothelial dysfunction in determining angina after percutaneous coronary intervention: Learning from pathophysiology to optimize treatment TAVI Represents an Anti-Inflammatory Therapy via Reduction of Shear Stress Induced, Piezo-1-Mediated Monocyte Activation
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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

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 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.

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