ADMA regulates angiogenesis: genetic and metabolic evidence
ADMA regulates angiogenesis: genetic and metabolic evidence
复制标题
DOI：
10.1191/1358863x05vm580oa
复制
发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Cooke, JP
中科院分区：
文献类型：
--
作者：
Achan, V;Ho, HK;Cooke, JP
内皮源性一氧化氮（NO）在血管生成因子的转导中起重要作用。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂。我们使用小鼠后肢缺血模型来研究ADMA水平的遗传或代谢变化是否会损害体内血管生成反应。在C57 BL/6 J小鼠、载脂蛋白E缺陷小鼠或过表达二甲基精氨酸二甲氨基水解酶（DDAH）的转基因小鼠中手术诱导后肢缺血。一些动物还用NOS拮抗剂L-硝基精氨酸或NO前体L-精氨酸治疗。通过毛细血管/肌细胞比率定量后肢骨骼肌中的血管生成。通过HPLC测量血浆或组织ADMA水平。在正常小鼠中，后肢缺血使组织ADMA增加两倍，并降低DDAH和NOS表达。这与手术后三天NOS活性降低（超过80%）有关。在第7天，DDAH表达增加3倍，组织ADMA水平下降，NOS活性增加7倍，而NOS表达没有增加到基线以上。在DDAH转基因小鼠中，后肢缺血时ADMA的升高和NOS活性的降低被钝化。载脂蛋白E小鼠的血浆ADMA水平升高（1.79 +/- 0.45 vs. 1.07 +/- 0.08 μ mol/l; p = 0.008）。在apo E-小鼠中，毛细血管指数在手术后7周内显著降低（0.25 +/- 0.05对0.62 +/- 0.08; p < 0.001）。高胆固醇血症对毛细血管指数的影响被L-精氨酸逆转，并且（在野生型小鼠中）通过施用NOS拮抗剂L-硝基精氨酸来模仿。总之，血浆和组织ADMA水平的代谢或遗传变化影响组织NO的产生和对缺血的血管生成反应。
Endothelium-derived nitric oxide (NO) plays an important role in transducing the effects of angiogenic factors. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We used a murine model of hindlimb ischemia to investigate whether genetic or metabolic changes in ADMA levels could impair angiogenic response in vivo. Hindlimb ischemia was surgically induced in C57BL/6J mice, apo E-deficient mice, or transgenic mice overexpressing dimethylarginine dimethylaminohydrolase (DDAH). Some animals were also treated with the NOS antagonist L-nitro-arginine, or the NO precursor L-arginine. Angiogenesis was quantified in the hindlimb skeletal muscle by capillary/myocyte ratio. Plasma or tissue ADMA levels were measured by HPLC. In normal mice, hindlimb ischemia increased tissue ADMA twofold, and reduced DDAH and NOS expression. This was associated with a reduced NOS activity (by over 80%) three days following surgery. On day seven, a threefold increase in DDAH expression and a fall in tissue ADMA levels were associated with a sevenfold increase in NOS activity, whereas NOS expression did not increase above baseline. In DDAH transgenic mice, the elevation of ADMA and decrement in NOS activity was blunted during hindlimb ischemia. Plasma ADMA levels were increased in apo E-mice (1.79 +/- 0.45 versus 1.07 +/- 0.08 mu mol/l; p = 0.008). Capillary index was significantly reduced in apo E-mice up to seven weeks after surgery (0.25 +/- 0.05 versus 0.62 +/- 0.08; p < 0.001). The effect of hypercholesterolemia on capillary index was reversed by L-arginine, and (in wild-type mice) mimicked by administration of the NOS antagonist L-nitro-arginine. In conclusion, metabolic or genetic changes in plasma and tissue ADMA levels affect tissue NO production and angiogenic response to ischemia.