Ceramide-induced impairment of endothelial function is prevented by CuZn superoxide dismutase overexpression

被引:26
作者
Didion, SP [1 ]
Faraci, FM
机构
[1] Univ Iowa, Carver Coll Med, Med Labs 2000, Dept Internal Med,Cardiovasc Ctr, Iowa City, IA 52242 USA
[2] Univ Iowa, Carver Coll Med, Ctr Cardiovasc, Iowa City, IA USA
关键词
carotid artery; genetically altered mice; nitric oxide; reactive oxygen species; SOD1;
D O I
10.1161/01.ATV.0000149868.74075.5d
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mumol/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 mu mol/L ACh relaxed arteries from nontransgenic mice by 96 +/- 4% and 52 +/- 5% in the presence of vehicle and 10 mu mol/L ceramide, respectively. In contrast, ceramide (1 or 10 mu mol/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.
引用
收藏
页码:90 / 95
页数:6
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