• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • br Disclosures br Acknowledgements This


    Acknowledgements This work was supported by the Natural Science Foundation of China (No. 81560587); the Fok Ying-Tong Education Foundation of China (No. 151107), the basic ability promotion project for young and middle-aged teachers in Universities in Guangxi (No. 2018KY1146) and the Joint Cultivation Base of Inovation & Entrepreneurship for Pharmaceutical Postgraduates (No. 20170703).
    Introduction Endothelial nitric oxide synthase (eNOS), located in membrane caveolae or on Golgi apparatus, serves as a critical enzyme in maintaining vascular hemostasis. However, under pathological conditions such as atherosclerosis, hypertension, diabetes, ischemia/reperfusion injury and smoking, eNOS becomes unstable and uncoupled as presented by production of O2− rather than nitric oxide (NO) [1]. Molecular mechanisms of eNOS uncoupling include deficiency of tetrahydrobiopterin (BH4) or BH4 oxidation, reduced intake of l-arginine, as well as posttranslational modification of eNOS, especially phosphorylation of eNOS Thr495 residue [2]. The latter is deemed as a ‘switch’ of eNOS uncoupling [3]. Shear stress (SS) is the friction force imposed by blood flow on endothelial surface. Physiological SS, ranged of 10–70 dyne/cm2 in arterial system, is atheroprotective, while low SS (<10 dyne/cm2) is implicated in atherosclerotic lesions embedment on arterial bifurcation or tortuous JIB-04 [4]. eNOS-derived NO is a pivotal signaling molecule in regulation of SS-mediated endothelial function and vascular tone [5,6]. Earlier, we reported that low SS increased O2− production [7] and eNOS Thr495 phosphorylation [8,9]. However, the underlying mechanisms attributed to low SS-induced endothelial dysfunction via eNOS uncoupling remains largely underreported. Autophagy is an evolutionally conserved process including self-eating, degrading and recycling long-lived proteins or damaged organelles, by which cells could adapt to nutrient deprivation and other harsh environment stress [10]. Upon sensing stressful signals, phagophore elongates and assembles autophagy-related gene complexes, followed by double membrane autophagosome formation. After that, autophagosome infused with lysosome and the contents of autolysosome were degraded by lysosome hydrolase [11]. The dynamic process of autophagy is described as autophagic flux. A body of evidences demonstrate that autophagy is an important cellular mechanism in regulation of endothelial function. Autophagy is implicated in normal endothelial function such as lipid metabolism [12], von Willebrand factor secretion [13], and angiogenesis [14]. Protective autophagy is activated in endothelial cells (ECs) in defense of exogenous insults [15]. Pharmacological agents, such as curcumin [16], gossypetin [17], as well as resveratrol [18], ameliorate deleterious effects imposed on ECs via enhanced autophagy. Furthermore, we previously demonstrated that autophagy inducer rapamycin appeased low SS-induced O2− production [19], indicating that autophagy may play an important role in maintaining endothelial homeostasis impaired by low SS, with unknown the precise corresponding mechanisms. Accordingly, we investigated the role of autophagy in regulation of eNOS uncoupling during low SS exposure.
    Materials and methods
    Discussion The main finding of this study is that autophagic flux impairment functions as a key regulator in low SS-induced eNOS uncoupling. We proposed that (1) redox regulation and eNOS acetylation were unlikely to be the biophysical mechanism underlying low SS (2 dyne/cm2) induced eNOS uncoupling; (2) instead of positively regulating autophagic flux, low SS conferred endothelial autophagic flux impairment; (3) low SS-induced eNOS uncoupling was secondary to autophagic flux impairment; (4) eNOS phosphorylation, regulated by autophagy, participated in low SS-induced eNOS uncoupling (Fig. 8).