title: Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation.
abstract: BACKGROUND
  Mitochondrial-derived hydrogen peroxide (H2O2) regulates flow-induced dilation (FID) in microvessels from patients with coronary artery disease. The relationship between ceramide, an independent risk factor for coronary artery disease and a known inducer of mitochondrial reactive oxygen species, and FID is unknown.
  
  
  OBJECTIVE
  We examined the hypothesis that exogenous ceramide induces a switch in the mediator of FID from nitric oxide to H2O2.
  
  
  RESULTS
  Internal diameter changes of resistance arterioles from human adipose and atrial tissue were measured by video microscopy. Mitochondrial H2O2 production was assayed in arterioles using mito peroxy yellow 1. Polyethylene glycol-catalase, rotenone, and Mito-TEMPO impaired FID in healthy adipose arterioles pretreated with ceramide, whereas N(ω)-nitro-l-arginine methyl ester had no effect. Mitochondrial H2O2 production was induced in response to flow in healthy adipose vessels pretreated with ceramide, and this was abolished in the presence of polyethylene glycol-catalase. Immunohistochemistry demonstrated ceramide accumulation in arterioles from both healthy patients and patients with coronary artery disease. N(ω)-nitro-l-arginine methyl ester reduced vasodilation to flow in adipose as well as atrial vessels from patients with coronary artery disease incubated with GW4869, a neutral sphingomyelinase inhibitor, whereas polyethylene glycol-catalase had no effect.
  
  
  CONCLUSIONS
  Our data indicate that ceramide has an integral role in the transition of the mediator of FID from nitric oxide to mitochondrial-derived H2O2 and that inhibition of ceramide production can revert the mechanism of dilation back to nitric oxide. Ceramide may be an important target for preventing and treating vascular dysfunction associated with atherosclerosis.
authors.affiliation: From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.).
authors.forename: Julie K
authors.initials: JK
authors.lastname: Freed
authors.affiliation: From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.).
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Beyer
authors.affiliation: From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.).
authors.forename: John A
authors.initials: JA
authors.lastname: LoGiudice
authors.affiliation: From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.).
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Hockenberry
authors.affiliation: From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.). dgutt@mcw.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply*; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D018715:Microscopy, Video; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine
keywords: ceramides; mitochondria; nitric oxide; reactive oxygen species; sphingomyelin phosphodiesterase