title: Hyperketonemia (acetoacetate) upregulates NADPH oxidase 4 and elevates oxidative stress, ICAM-1, and monocyte adhesivity in endothelial cells.
abstract: OBJECTIVE
  The incidence of developing microvascular dysfunction is significantly higher in type 1 diabetic (T1D) patients. Hyperketonemia (acetoacetate, β-hydroxybutyrate) is frequently found along with hyperglycemia in T1D. Whether hyperketonemia per se contributes to the excess oxidative stress and cellular injury observed in T1D is not known.
  
  
  METHODS
  HUVEC were treated with ketones in the presence or absence of high glucose for 24 h. NOX4 siRNA was used to specifically knockdown NOX4 expression in HUVEC.
  
  
  RESULTS
  Ketones alone or in combination with high glucose treatment cause a significant increase in oxidative stress, ICAM-1, and monocyte adhesivity to HUVEC. Using an antisense approach, we show that ketone induced increases in ROS, ICAM-1 expression, and monocyte adhesion in endothelial cells were prevented in NOX4 knockdown cells.
  
  
  CONCLUSIONS
  This study reports that elevated levels of ketones upregulate NOX, contributing to increased oxidative stress, ICAM-1 levels, and cellular dysfunction. This provides a novel biochemical mechanism that elucidates the role of hyperketonemia in the excess cellular injury in T1D. New drugs targeting inhibition of NOX seems promising in preventing higher risk of complications associated with T1D.
authors.affiliation: Departments of Pediatrics and Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Kanikarla-Marie
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000633:toxicity; D000090:Acetoacetates / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000090:Acetoacetates; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; C016635:acetoacetic acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D005947:Glucose; D020155:3-Hydroxybutyric Acid