Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase.
Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase.
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作者：
Sudhahar V;Urao N;Oshikawa J;McKinney RD;Llanos RM;Mercer JF;Ushio-Fukai M;Fukai T
氧化应激和内皮功能障碍有助于糖尿病的血管并发症。胞外超氧化物歧化酶（SOD3）是通过铜转运体ATP7A获得铜的关键抗氧化酶之一。SOD3由血管平滑肌细胞（VSMCs）分泌并锚定在内皮细胞表面。SOD3和ATP7A在1型糖尿病（T1DM）内皮功能障碍中的作用尚不清楚。在这里，我们发现SOD3的特异性活性下降，而不是SOD1，这与链脲佐菌素诱导和遗传诱导的ins2秋田T1DM小鼠主动脉中O2•−产生增加有关。外源性铜部分恢复了离体T1DM血管中SOD3的活性。功能上，乙酰胆碱诱导的内皮依赖性松弛在T1DM肠系膜动脉中受损，可通过SOD模拟时间或SOD3基因转移来挽救。机制上，ATP7A在T1DM血管中的表达显著降低，而其他铜转运蛋白没有改变。在过表达ATP7A的转基因小鼠中，t1dm诱导的内皮功能障碍和SOD3活性降低得以恢复。此外，与T1DM小鼠相比，sod3缺陷T1DM小鼠或ATP7A突变T1DM小鼠内皮功能障碍和血管O2•−产生增加。这些影响部分是由于T1DM小鼠的低胰岛素血症，因为胰岛素治疗，而不是高葡萄糖，增加了VSMCs中ATP7A的表达，并恢复了T1DM血管类器官培养中SOD3的活性。综上所述，ATP7A蛋白表达的降低导致SOD3活性受损，导致T1DM血管中O2•−产生过多和内皮功能障碍。因此，恢复铜转运体功能是氧化应激依赖性血管和代谢疾病的重要治疗方法。
Oxidative stress and endothelial dysfunction contribute to vascular complication in diabetes. Extracellular superoxide dismutase (SOD3) is one of the key antioxidant enzymes that obtains copper via copper transporter ATP7A. SOD3 is secreted from vascular smooth muscles cells (VSMCs) and anchors at the endothelial surface. The role of SOD3 and ATP7A in endothelial dysfunction in type 1 diabetes mellitus (T1DM) is entirely unknown. Here we show that the specific activity of SOD3, but not SOD1, is decreased, which is associated with increased O2•− production in aortas of streptozotocin-induced and genetically induced Ins2Akita T1DM mice. Exogenous copper partially rescued SOD3 activity in isolated T1DM vessels. Functionally, acetylcholine-induced, endothelium-dependent relaxation is impaired in T1DM mesenteric arteries, which is rescued by SOD mimetic tempol or gene transfer of SOD3. Mechanistically, ATP7A expression in T1DM vessels is dramatically decreased whereas other copper transport proteins are not altered. T1DM-induced endothelial dysfunction and decrease of SOD3 activity are rescued in transgenic mice overexpressing ATP7A. Furthermore, SOD3-deficient T1DM mice or ATP7A mutant T1DM mice augment endothelial dysfunction and vascular O2•− production versus T1DM mice. These effects are in part due to hypoinsulinemia in T1DM mice, since insulin treatment, but not high glucose, increases ATP7A expression in VSMCs and restores SOD3 activity in the organoid culture of T1DM vessels. In summary, a decrease in ATP7A protein expression contributes to impaired SOD3 activity, resulting in O2•− overproduction and endothelial dysfunction in blood vessels of T1DM. Thus, restoring copper transporter function is an essential therapeutic approach for oxidant stress–dependent vascular and metabolic diseases.
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影响因子：
20.1
作者：
Jeney, V;Itoh, S;Fukai, T
通讯作者：
Fukai, T
影响因子：
7.3
作者：
Kamata, K;Kobayashi, T
通讯作者：
Kobayashi, T
影响因子：
4.1
作者：
ADACHI, T;OHTA, H;MARKLUND, SL
通讯作者：
MARKLUND, SL
DOI：
10.1152/ajpregu.00806.2005
发表时间：
2006-05-01
影响因子：
2.8
作者：
Ke, BX;Llanos, RM;Mercer, JFB
通讯作者：
Mercer, JFB
影响因子：
82.9
作者：
通讯作者：
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