Impaired vascular function in sepsis-surviving rats mediated by oxidative stress and Rho-Kinase pathway.
Impaired vascular function in sepsis-surviving rats mediated by oxidative stress and Rho-Kinase pathway.
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DOI：
10.1016/j.redox.2016.09.016
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发表时间：
2016-12
期刊：
影响因子：
11.4
通讯作者：
da Silva-Santos, Jose Eduardo
中科院分区：
文献类型：
--
作者：
de Souza, Priscila;Guarido, Karla Lorena;Scheschowitsch, Karin;da Silva, Luisa Mota;Werner, Maria Fernanda;Assreuy, Jamil;da Silva-Santos, Jose Eduardo
我们研究了盲肠结扎穿刺（CLP）模型诱发的严重脓毒症成年大鼠幸存者的内皮和血管功能的长期变化。为此，用 14 号针将雄性 Wistar 大鼠（200-350 克）的盲肠刺穿一次（非刺穿孔）。以这种方式执行，前 72 小时内的死亡率达到了 30% 左右。幸存者以及年龄匹配的对照大鼠（未接受 CLP）在我们的饲养室中饲养 60 天（S60 组），并对胸降主动脉进行功能、组织学、生化或分子分析。与对照组的血管相比，脓毒症幸存的 S60 组获得的内皮完整的主动脉环表现出血管紧张素 II 诱导的收缩增加，同时内源性超氧化物歧化酶活性降低，活性氧生成增加，酪氨酸硝化水平增加。超氧化物清除剂超氧化物歧化酶和 tempol 以及抗氧化剂夹竹桃麻素能够避免 S60 组主动脉环中血管紧张素 II 的这种增强的收缩性。此外，S60 组的主动脉环对 Rho 激酶 (ROCK) 抑制剂 Y-27632 的敏感性降低。免疫印迹分析显示 S60 大鼠血管中 RhoA 和 ROCK II 增强，肌球蛋白磷酸酶靶亚基 1 磷酸化水平高。总之，脓毒症存活大鼠的主动脉环表现出由活性氧产生增加介导的内皮功能障碍，进而降低一氧化氮的生物利用度并增加过氧亚硝酸盐的形成，并增强 RhoA-ROCK 介导的钙敏化，导致对血管紧张素 II 的收缩反应增强。值得注意的是，这是第一项研究证明脓毒症存活大鼠的脉管系统存在长期功能障碍，这种功能障碍在急性脓毒症损伤后发生或持续存在。脓毒症存活大鼠的血管对血管紧张素 II 产生增强的收缩反应。超氧化物清除剂超氧化物歧化酶和 tempol 可以避免这种过度反应。在这些血管中，血管紧张素 II 产生的活性氧物质增强。脓毒症存活大鼠的血管呈现出更高程度的酪氨酸硝化。脓毒症存活大鼠的主动脉中 RhoA-Rho-激酶途径的活性增强。
We investigated long-lasting changes in endothelial and vascular function in adult rat survivors of severe sepsis induced by cecal ligation and puncture (CLP) model. For this, male Wistar rats (200–350 g) had their cecum punctured once (non-transfixing hole) with a 14-gauge needle. Performed in this way, a mortality rate around 30% was achieved in the first 72 h. The survivors, together with age-matched control rats (not subjected to CLP), were maintained in our holding room for 60 days (S60 group) and had the descending thoracic aorta processed for functional, histological, biochemical or molecular analyses. Endothelium-intact aortic rings obtained from sepsis-surviving S60 group displayed increased angiotensin II-induced contraction, accompanied by decreased activity of the endogenous superoxide dismutase, augmented reactive oxygen species generation, and increased levels of tyrosine nitration compared with vessels from control group. The superoxide scavengers superoxide dismutase and tempol, and the antioxidant apocynin, were able to avoid this enhanced contractility to angiotensin II in aortic rings from the S60 group. In addition, aortic rings from the S60 group presented reduced sensitivity to Y-27632, a Rho-kinase (ROCK) inhibitor. Immunoblot analyses revealed augmented RhoA and ROCK II, and high levels of phosphorylation of myosin phosphatase target subunit 1 in vessels from S60 rats. In conclusion, aortic rings from sepsis-surviving rats display endothelial dysfunction mediated by the increased production of reactive oxygen species, which in turn reduces the bioavailability of nitric oxide and increases the formation of peroxynitrite, and enhances RhoA-ROCK-mediated calcium sensitization, leading to augmented contractile responses to angiotensin II. Notably, this is the first study demonstrating long-term dysfunction in the vasculature of sepsis-surviving rats, which take place or remain beyond the acute septic insult. Vessels from sepsis-surviving rats develop enhanced contractile responses to angiotensin II. This hyperreactivity is avoided by the superoxide scavengers superoxide dismutase and tempol. Generation of reactive oxygen species by angiotensin II is enhanced in these vessels. Vessels from sepsis-surviving rats present an augmented degree of tyrosine nitration. The activity of the RhoA-Rho-kinase pathway is enhanced in the aorta from sepsis-surviving rats.
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影响因子：
1.8
作者：
Contrin, Ligia Marcia;Paschoal, Vania Del'Arco;Lobo, Suzana Margareth Ajeje
通讯作者：
Lobo, Suzana Margareth Ajeje
DOI：
10.1016/s0302-4598(98)00072-5
发表时间：
1998-03-01
期刊：
BIOELECTROCHEMISTRY AND BIOENERGETICS
影响因子：
--
作者：
Gao, RM;Yuan, ZB;Gao, XR
通讯作者：
Gao, XR
影响因子：
37.8
作者：
Halcox, JPJ;Schenke, WH;Quyyumi, AA
通讯作者：
Quyyumi, AA
影响因子：
--
作者：
El-Remessy AB;Tawfik HE;Matragoon S;Pillai B;Caldwell RB;Caldwell RW
通讯作者：
Caldwell RW
影响因子：
38.9
作者：
Laupland, KB;Zygun, DA;Fick, GH
通讯作者：
Fick, GH