title: 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis).
abstract: BACKGROUND
  There is a significantly higher incidence of cardiovascular disease (CVD) among type 1 diabetic (T1D) patients than among non-diabetic subjects. T1D is associated with hyperketonemia, a condition with elevated blood levels of ketones, in addition to hyperglycemia. The biochemical mechanism by which vitamin D (VD) may reduce the risk of CVD is not known. This study examines whether VD can be beneficial in reducing hyperketonemia (acetoacetate, AA) induced oxidative stress in endothelial cells.
  
  
  METHODS
  HUVEC were pretreated with 1,25(OH)2D3, and later exposed to the ketone body acetoacetate.
  
  
  RESULTS
  The increases in ROS production, ICAM-1 expression, MCP-1 secretion, and monocyte adhesion in HUVEC treated with AA were significantly reduced following treatment with 1,25(OH)2D3. Interestingly, an increase in glutathione (GSH) levels was also observed with 1,25(OH)2D3 in ketone treated cells. The effects of 1,25(OH)2D3 on GSH, ROS, and monocyte-endothelial adhesion were prevented in GCLC knockdown HUVEC. This suggests that 1,25(OH)2D3 inhibits ROS, MCP-1, ICAM-1, and adherence of monocytes mediated by the upregulation of GCLC and GSH.
  
  
  CONCLUSIONS
  This study provides evidence for the biochemical mechanism through which VD supplementation may reduce the excess monocyte adhesion to endothelium and inflammation associated with T1D.
authors.affiliation: Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Kanikarla-Marie
authors.affiliation: Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. Electronic address: sjain@lsuhsc.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D000090:Acetoacetates / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002448:Cell Adhesion; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007662:Ketosis / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000090:Acetoacetates; D016207:Cytokines; D018167:Receptors, Calcitriol; D018799:Intercellular Adhesion Molecule-1; C016635:acetoacetic acid; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase; D002117:Calcitriol; D005978:Glutathione
keywords: 1,25(OH)(2)D3; Endothelium; Ketones; Oxidative stress; Type 1 diabetes; Vitamin D