on November 4, 2004
Published online before print November 4, 2004, doi: 10.1161/01.ATV.0000149868.74075.5d
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Submitted on February 25, 2004
Accepted on October 27, 2004
Ceramide-Induced Impairment of Endothelial Function Is Prevented by CuZn Superoxide Dismutase Overexpression
Sean P. Didion * and Frank M. Faraci
From the Departments of Internal Medicine (S.P.D., F.M.F.) and Pharmacology (F.M.F.), Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City.
* To whom correspondence should be addressed. E-mail: sean-didion{at}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 µmol/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 µmol/L ACh relaxed arteries from nontransgenic mice by 96±4% and 52±5% in the presence of vehicle and 10 µmol/L ceramide, respectively. In contrast, ceramide (1 or 10 µmol/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.
Key words: carotid artery • genetically altered mice • nitric oxide • reactive oxygen species • SOD1
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