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  • It is noteworthy that little


    It is noteworthy that little is known as to the role of autophagy in regulation of eNOS phosphorylation and eNOS uncoupling. eNOS monomers, but not eNOS dimers could be degraded by ubiquitination [39], harbingering the existence of protein degradation pathways in modulation of eNOS turnover and activity. Recently, Bharath et al. found that using RNA interfering to suppress autophagy could reduce eNOS Ser 1177 phosphorylation and NO release induced by physiological SS (20 dyne/cm2) [40]. In our study, restoring autophagic flux repressed low SS-induced eNOS Thr495 activation and increased NO releasing, suggesting low SS-induced eNOS uncoupling is mediated by autophagy. Phorbol 12-myristate 13-acetate (PMA) is the agonist of PKC, a known protein to phosphorylate eNOS Thr 495 residues. As expected, eNOS Thr 495 phosphorylation induced by PMA was also mediated by autophagy. Therefore, the involvement of classical PKC in low SS induced autophagic flux impairment and eNOS uncoupling needs investigation in the future. Phosphorylation of eNOS Ser1177 and Thr495 residues exhibited reciprocal effects on eNOS uncoupling. Despite eNOS Ser1177 was not conspicuously stimulated by low SS, add-on rapamycin increased eNOS Ser1177 phosphorylation significantly, which favored eNOS recoupling during low SS exposure. In line with that, Lin et al. found acute rapamycin treatment induced eNOS Ser1177 phosphorylation and NO release in Zinc Pyrithione endothelium and restored brain vascular integrity and function [41]. In addition, it was reported that restoration of autophagy by spermidine induced NO generation in ECs exposed to high glucose [42]. Thus, eNOS phosphorylation might be an important mechanism in autophagy-mediated eNOS uncoupling in low SS situation. Acetylation of eNOS constitutes another important posttranslational regulation of eNOS activity. Although acetylation of Atg3 was reported to regulate autophagy [43] and eNOS deacetylation was promoted by physiological shear stress [24], little is unknown considering the influence of autophagy on protein acetylation as well as impact of low SS on eNOS acetylation. In this study, we found both autophagy and low SS had no significant impact on eNOS acetylation.
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    We noticed that several recent articles published in the from 2016 to 2018 are correlated with each other, and they put forward a novel mechanism elucidating the potential linkage between diabetes mellitus (DM) and cardiovascular diseases. , Larsson et al. clarified that both type 1 and type 2 DM are associated with the increasing risks of myocardial infarction, heart failure, ischemic stroke, . []. However, their complicated mechanisms haven't been validated evidently. , Costantino et al. proved that Pin1 promotes high glucose-induced vascular dysfunction in human aortic endothelial cells and mice, which can be blocked by juglone, a Pin1 inhibitor []. , Liu et al. found that myocardial Pin1 significantly increases in diabetic mice, implying that high-level blood glucose may stimulate Pin1 over-expression in cardiovascular tissues []. , endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) are well-known for preventing atherosclerosis and protecting the cardiovascular system, whereas Kennard et al. revealed that Pin1 directly binds to eNOS and thus inhibits eNOS activity resulting in a decreased NO bioactivity [,].
    Introduction Among NO-synthases (NOS) the endothelial isoform (eNOS) significantly contributes to the regulation of BP as hypertension is the most obvious phenotype in 4 different strains of eNOS-deficient mice (eNOS-KO) suggesting that other physiologic systems regulating BP cannot compensate for the absence of eNOS [1], [2], [3], [4]. Likewise, hypertension develops following treatment with NOS-inhibitors such as monomethyl arginine (L-NMMA) or l-nitroarginine (L-NA) in rabbits [5], mice [1], [6], and humans [5], [7]. Based on these findings it is generally assumed that the lack of vasodilation by endothelial NO is an important underlying cause [1], [2], i.e. that hypertension in eNOS-KO is caused by the lack of endothelium-dependent NO-induced vasodilation.