Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circ Res 2014 Aug 15;115(5):525-32
Date
06/13/2014Pubmed ID
24920698Pubmed Central ID
PMC4640193DOI
10.1161/CIRCRESAHA.115.303881Scopus ID
2-s2.0-84906100241 (requires institutional sign-in at Scopus site) 102 CitationsAbstract
RATIONALE: 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.
METHODS AND 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.
Author List
Freed JK, Beyer AM, LoGiudice JA, Hockenberry JC, Gutterman DDAuthors
Andreas M. Beyer PhD Professor in the Medicine department at Medical College of WisconsinJulie K. Freed MD, PhD Vice Chair, Associate Professor in the Anesthesiology department at Medical College of Wisconsin
John A. LoGiudice MD Professor in the Plastic Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adipose TissueAdult
Aged
Antioxidants
Arterioles
Case-Control Studies
Coronary Artery Disease
Coronary Circulation
Coronary Vessels
Enzyme Inhibitors
Female
Humans
Hydrogen Peroxide
Male
Microcirculation
Microscopy, Video
Middle Aged
Mitochondria
Nitric Oxide
Nitric Oxide Synthase
Regional Blood Flow
Signal Transduction
Sphingomyelin Phosphodiesterase
Sphingosine
Time Factors
Vasodilation
