Oxidative stress and COX cause hyper-responsiveness in vascular smooth muscle of the femoral artery from diabetic rats
Oxidative stress and COX cause hyper-responsiveness in vascular smooth muscle of the femoral artery from diabetic rats
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DOI：
10.1038/bjp.2008.110
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发表时间：
2008-06-01
影响因子：
7.3
通讯作者：
Vanhoutte, P. M.
中科院分区：
文献类型：
--
作者：
Shi, Y.;Vanhoutte, P. M.
背景和目的：为探讨链脲佐菌素（STZ）诱导的糖尿病大鼠血管平滑肌功能障碍。实验方法：将去内皮的股动脉环悬挂于器官室中，进行等长张力记录。使用共聚焦显微镜用2 '，7'-二氯二氢荧光素二乙酸酯测量氧衍生自由基的产生。关键结果：U46619和苯丙氨酸的浓度-反应曲线左移，而不是KCl，表明在糖尿病细胞膜受体的超敏性。外源性氧自由基引起糖尿病大鼠股动脉血管收缩。用夹竹桃麻素（NADPH氧化酶抑制剂）慢性治疗和急性暴露于MnTMPyP（SOD/过氧化氢酶模拟物）使反应正常化。过氧化氢酶活性和总谷胱甘肽水平降低动脉链脲佐菌素治疗的大鼠，确认氧化还原异常。链脲佐菌素处理的大鼠动脉的基础氧化状态较高，而夹竹桃素和链脲佐菌素处理的大鼠动脉的基础氧化状态降低，这表明糖尿病的功能变化是由于氧化应激的慢性增加。在链脲佐菌素处理的大鼠的动脉中，考克斯-1和/或考克斯-2的抑制剂防止了超敏反应，并减少了由苯丙氨酸和U46619引起的氧化应激的增加，这表明两种亚型都有助于平滑肌功能障碍。蛋白质的表达考克斯-1和考克斯-2链脲佐菌素治疗的大鼠动脉中增加，并减少在制备的夹竹桃素和链脲佐菌素治疗rats.Conclusions和影响：慢性糖尿病和由此产生的氧化应激增加激活生产的COX衍生的血管收缩剂前列腺素类引起的血管平滑肌超敏反应。
Background and purpose: To investigate the dysfunction of vascular smooth muscle in streptozotocin-induced diabetic rats.Experimental approach: Rings without endothelium of femoral arteries were suspended in organ chambers for isometric tension recording. The production of oxygen-derived free radicals was measured with 2',7'-dichlorodihydrofluorescein diacetate using confocal microscopy. The protein expressions were measured by western blotting.Key results: The concentration-response curves to U46619 and phenylephrine, but not that to KCI, were shifted to the left, suggesting a hypersensitivity of cell membrane receptors in diabetes. Exogenous oxygen-derived free radicals induced greater vasoconstrictions in the femoral artery from diabetic rats. Chronic treatment with apocynin (inhibitor of NADPH oxidase) and acute exposure to MnTMPyP (SOD/catalase mimetic) normalized the response. The catalase activity and the total glutathione level were reduced in arteries from streptozotocin-treated rats, confirming a redox abnormality. The basal oxidative state was higher in arteries from streptozotocin-treated rats and reduced in arteries from apocynin-and streptozotocin-treated rats, suggesting that the functional changes in diabetes are due to a chronic increase in oxidative stress. In the arteries of streptozotocin-treated rats, inhibitors of COX-1 and/or COX-2 prevented the hypersensitivity and reduced the increase in oxidative stress caused by phenylephrine and U46619, suggesting that both isoforms contribute to the smooth muscle dysfunction. The expression of proteins for COX-1 and COX-2 was increased in arteries of streptozotocin-treated rats and reduced in preparations of apocynin-and streptozotocin-treated rats.Conclusions and implications: Chronic diabetes and the resulting increased oxidative stress activate the production of COX-derived vasoconstrictor prostanoids causing hypersensitivity of vascular smooth muscle.