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Ceramide-induced impairment of endothelial function is prevented by CuZn superoxide dismutase overexpression
Sean P Didion1, Frank M Faraci
1Department of Internal Medicine, 2000 Medical Laboratories, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. sean-didion@uiowa.edu
Objective:
Ceramide is an important intracellular second messenger that may also increase superoxide. The goal of this study was to determine whether overexpression of CuZn superoxide dismutase (SOD) protects against ceramide-induced increases in vascular superoxide and endothelial dysfunction.
Methods And Results:
Carotid arteries from CuZnSOD-transgenic (CuZnSOD-Tg) and nontransgenic littermates were examined in vitro. Immunohistochemistry confirmed that CuZnSOD protein was greater in carotid artery from CuZnSOD-Tg compared with nontransgenic mice. Ceramide (N-acetyl-d-sphingosine; 1 and 10 micromol/L) produced concentration-dependent impairment (P<0.05) of vasorelaxation in response to the endothelium-dependent agonist acetylcholine (ACh) in nontransgenic mice. For example, 100 micromol/L ACh relaxed arteries from nontransgenic mice by 96+/-4% and 52+/-5% in the presence of vehicle and 10 micromol/L ceramide, respectively. In contrast, ceramide (1 or 10 micromol/L) had no effect (P>0.05) on responses of carotid artery to ACh in CuZnSOD-Tg mice. Ceramide had no effect on nitroprusside- or papaverine-induced relaxation in CuZnSOD-Tg or nontransgenic mice. Ceramide increased superoxide in arteries from nontransgenic vessels, and this effect was prevented by polyethyleneglycol-SOD (50 U/mL) or overexpression of CuZnSOD.
Conclusions:
These results suggest that ceramide-induced increases in superoxide impair endothelium-dependent relaxation, and that select overexpression of the CuZn isoform of SOD prevents ceramide-induced oxidative stress in vessels.
