title: d-Chiro inositol ameliorates endothelial dysfunction via inhibition of oxidative stress and mitochondrial fission.
abstract: d-chiro inositol (DCI), an isomer of inositol, possesses anti-oxidative and endothelial protective properties. The mechanism by which DCI prevents endothelial dysfunction was investigated, with emphasis on oxidative stress.
  
  
  
  DCI was found to inhibit NOX4 induction and enhance Nrf2 activity in palmitate (PA)-stimulated cells, showing that DCI prevents oxidative stress. DCI suppressed Ser616 phosphorylation and increased Ser637 phosphorylation of Drp1 and inhibited PA-induced mitochondrial fission. Knockdown of Drp1 attenuated NOX4 over-expression and increased the inhibitory effect of DCI. In addition, DCI enhanced AMPK activity through the LKB1-dependent pathway. AMPK knockdown diminished the inhibitory effect of DCI on Drp1/NOX4 induction, indicating that AMPK is essential for Drp1 and NOX4 suppression by DCI. As a result, DCI inhibited cell apoptosis against PA insults. Consistent with the effects observed in cells, DCI reversed endothelial dysfunction in rat aorta rings under lipid-challenged conditions. In high fat-fed mice, oral administration of DCI inhibited Drp1/NOX4 induction and enhanced NO generation in the aortic endothelium, confirming its protective role in endothelial function in vivo.
  
  
  
  Drp1 activation-induced mitochondrial fission and NOX4 over-expression are associated with endothelial injury. DCI prevented endothelial dysfunction by inhibiting oxidative stress and mitochondrial fission in an AMPK-dependent manner.
authors.affiliation: College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, China.
authors.forename: Bobo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China.
authors.forename: Xudan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute of agricultural products processing, Shanxi Academy of Agriculture Sciences, Taiyuan, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Peng
authors.affiliation: College of Agronomy, Northwest A&F University, Yangling, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D034281:Dynamins; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007294:Inositol / Q000494:pharmacology*; D008297:Male; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D007294:Inositol; D000074663:NADPH Oxidase 4; C498910:NOX4 protein, human; C498911:Nox4 protein, rat; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: AMPK; Endothelial dysfunction; Mitochondrial fission; NOX4 oxidase; d-chiro inositol