Overexpression of dimethylarginine dimethylaminohydrolase inhibits asymmetric dimethylarginine-induced endothelial dysfunction in the cerebral circulation
Overexpression of dimethylarginine dimethylaminohydrolase inhibits asymmetric dimethylarginine-induced endothelial dysfunction in the cerebral circulation
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DOI：
10.1161/strokeaha.107.490631
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发表时间：
2008-01-01
期刊：
影响因子：
8.3
通讯作者：
Faraci, Frank M.
中科院分区：
文献类型：
--
作者：
Dayoub, Hayan;Rodionov, Roman;Faraci, Frank M.
背景与目的不对称二甲基精氨酸(ADMA)是一氧化氮合酶(NOS)的内源性抑制物。血浆ADMA水平升高与心血管疾病有关。ADMA由二甲基精氨酸二甲氨基水解酶(DDAHs)水解。本研究的目的是确定在转基因(DDAH-1-TG)小鼠中过表达人DDAH-1是否抑制ADMA的血管效应。方法：使用非转基因(非TG)和DDAH-1-TG小鼠，比较了ADMA存在或不存在时，颈动脉和主动脉(体外)和脑小动脉(体内)的反应。结果-Western blotting显示DDAH-1-TG小鼠血管中DDAH-1的表达明显增加。DDAH-1-TG组小鼠血浆ADMA水平较非TG组小鼠降低约50%(0.19+/-0.02vs0.37+/-0.04mU·mol/L，P<；0.05)。主动脉对一氧化氮合酶抑制物--硝基-L-精氨酸甲酯的收缩(NO的基础生成指标)在DDAH-1-TG小鼠中较对照组增加(50+/-4%比34+/-4%，P<；0.05)。与对照组相比，DDAH-1-TG组小鼠颈动脉对乙酰胆碱(一种内皮依赖激动剂)的松弛作用增强(10MU/L L组松弛程度分别为74+/-6%和59+/-5%，P<；0.05)。阿霉胺(100mU/L)对非甘油三酯和DDAH-1-甘油三酯小鼠血管对乙酰胆碱的反应均有损伤作用，但两品系之间的相对差异仍然存在。各组对内皮非依赖性NO供体硝普钠的反应相似。在体内，ADMA(10 mU·m o l/L)可使非TG小鼠脑小动脉对乙酰胆碱的反应性降低约70%(P<；0.05)，而DDAH-1-TG小鼠则基本不存在这种抑制作用。结论--首次发现DDAH-1过表达可增加血管基础NO水平，并对ADMA诱导的脑循环内皮细胞功能障碍具有保护作用。
Background and Purpose-Asymmetric dimethylarginine ( ADMA) is an endogenous inhibitor of nitric oxide synthase ( NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA.Methods-Using nontransgenic (non-Tg) and DDAH-1-Tg mice, we compared responses of the carotid artery and aorta ( in vitro) and of the cerebral arterioles ( in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured.Results-Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1-Tg mice. Plasma levels of ADMA were reduced by approximate to 50% in DDAH-1-Tg mice compared with non-Tg mice ( 0.19 +/- 0.02 vs 0.37 +/- 0.04 mu mol/L, P < 0.05). Contraction of the aorta to nitro-L-arginine methyl ester ( an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1-Tg mice compared with controls ( 50 +/- 4% vs 34 +/- 4%, P < 0.05). Relaxation of the carotid artery to acetylcholine ( an endothelium-dependent agonist) was enhanced in DDAH-1-Tg animals compared with control mice ( relaxation of 74 +/- 6% vs 59 +/- 5%, respectively, in response to 10 mu mol/L acetylcholine, P < 0.05). ADMA ( 100 mu mol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1-Tg mice, but the relative difference between the 2 strains remained. Responses to the endothelium-independent NO donor nitroprusside were similar in all groups. In vivo, ADMA ( 10 mu mol/L) reduced responses of the cerebral arterioles to acetylcholine by approximate to 70% in non-Tg mice ( P < 0.05), and this inhibitory effect was largely absent in DDAH-1-Tg mice.Conclusions-These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation.