Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II
Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II
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DOI：
10.1007/s00726-011-1136-3
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发表时间：
2012-08-01
期刊：
影响因子：
3.5
通讯作者：
Luecke, Thomas
中科院分区：
文献类型：
--
作者：
Chobanyan-Juergens, Kristine;Fuchs, Anne-Jule;Luecke, Thomas
不对称二甲基精氨酸（ADMA）系统浓度在高胆固醇血症成人中升高，并导致一氧化氮（NO）依赖性内皮功能障碍。关键的adma水解酶二甲基精氨酸二甲氨基水解酶（DDAH）活性降低可能与此有关。然而，ADMA/DDAH/NO通路在儿童高胆固醇血症中的作用尚未得到研究。我们研究了64名II型高胆固醇血症（HCh-II）儿童和54名正常胆固醇血症（NCh）儿童（平均+/- A SD；年龄，年龄：11.1 +/- A 3.5 vs 11.9 +/- A 4.6）。采用GC-MS/MS法测定血浆和尿液ADMA。采用气相色谱-质谱法测定尿液中二甲胺（DMA）、二甲胺代谢物、肌酐、亚硝酸盐和硝酸盐。计算尿液中DMA/ADMA的摩尔比，以估计全身DDAH活性。HCh-II和NCh患儿ADMA血药浓度（平均+/- A SD； nM: 571 +/- A 85 vs 542 +/- A 110, P = 0.17）和ADMA尿排泄率（平均+/- A SD: 7.1 +/- A 2 vs 7.2 +/- A 3 mu mol/mmol肌酐，P = 0.6）相似。HCh-II患儿的DMA排泄率[中位数（25 -75百分位数）：56.3（46.4-109.1）比45.2 (22.2-65.5)mu mol/mmol肌酐，P = 0.0004]和DMA/ADMA摩尔比[中位数（25 -75百分位数）：9.2（6.0-16.3）比5.4 (3.8-9.4),P = 0.0004]与NCh患儿相比，HCh-II患儿的DMA排泄率[中位数（25 -75百分位数）：5.4 (P = 0.0004]略有升高，但有统计学意义。两组血浆和尿中亚硝酸盐和硝酸盐含量相似。在HCh-II中，与NCh相比，全身DDAH活性升高。用药物治疗高胆固醇血症的HCh-II儿童的血浆ADMA水平低于未治疗的HCh-II或NCh儿童，可能是通过增加DDAH活性。治疗和未治疗的HCh-II患儿之间的差异不是由于年龄的差异。总之，HCh-II型患儿血浆ADMA水平没有升高，主要是由于DDAH活性明显增加。虽然这可能会限制内皮功能障碍的发展，但尚不清楚这是否可能是药物诱导的，还是代表HCh-II儿童的原发性变化。
Asymmetric dimethylarginine (ADMA) systemic concentrations are elevated in hypercholesterolemic adults and contribute to nitric oxide (NO) dependent endothelial dysfunction. Decreased activity of the key ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase (DDAH) may be involved. Yet, the ADMA/DDAH/NO pathway has not been investigated in childhood hypercholesterolemia. We studied 64 children with hypercholesterolemia type II (HCh-II) and 54 normocholesterolemic (NCh) children (mean +/- A SD; age, years: 11.1 +/- A 3.5 vs. 11.9 +/- A 4.6). Plasma and urine ADMA was measured by GC-MS/MS. Dimethylamine (DMA), the ADMA metabolite, creatinine, nitrite and nitrate in urine were measured by GC-MS. The DMA/ADMA molar ratio in urine was calculated to estimate whole body DDAH activity. ADMA plasma concentration (mean +/- A SD; nM: 571 +/- A 85 vs. 542 +/- A 110, P = 0.17) and ADMA urinary excretion rate (mean +/- A SD: 7.1 +/- A 2 versus 7.2 +/- A 3 mu mol/mmol creatinine, P = 0.6) were similar in HCh-II and NCh children. Both DMA excretion rate [median (25th-75th percentile): 56.3 (46.4-109.1) vs. 45.2 (22.2-65.5) mu mol/mmol creatinine, P = 0.0004] and DMA/ADMA molar ratio [median (25th-75th percentile): 9.2 (6.0-16.3) vs. 5.4 (3.8-9.4), P = 0.0004] were slightly but statistically significantly increased in HCh-II children compared to NCh children. Plasma and urinary nitrite and nitrate were similar in both groups. In HCh-II whole body DDAH activity is elevated as compared to NCh. HCh-II children treated with drugs for hypercholesterolemia had lower plasma ADMA levels than untreated HCh-II or NCh children, presumably via increased DDAH activity. Differences between treated and untreated HCh-II children were not due to differences in age. In conclusion, HCh-II children do not have elevated ADMA plasma levels, largely due to an apparent increase in DDAH activity. While this would tend to limit development of endothelial dysfunction, it is not clear whether this might be medication-induced or represent a primary change in HCh-II children.