The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension.
The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension.
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DOI：
10.1186/cc12809
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发表时间：
2013-07-11
期刊：
影响因子：
--
通讯作者：
Castrop H
中科院分区：
文献类型：
--
作者：
Mederle K;Schweda F;Kattler V;Doblinger E;Miyata K;Höcherl K;Oike Y;Castrop H
脓毒症患者的低血压是由于血容量不足、血管舒张和血管收缩剂（如血管紧张素 II）反应性低下所致。 AT1 受体相关蛋白 1 (Arap1) 在血管平滑肌细胞中表达，并在体外增加 AT1 受体的表面表达。我们假设 Arap1 的失调可能导致内毒素血症期间血管对血管紧张素 II 的反应性低下。 Arap1 缺陷小鼠被用来评估 Arap1 在脓毒症引起的低血压中的作用。使用分离的灌注肾作为体外模型来确定 Arap1 与血管阻力和血管紧张素 II 敏感性的相关性。在内毒素血症期间，两种基因型的平均动脉血压（MAP）均下降，与+/+小鼠相比，Arap1-/-中脓毒症引起的低血压的时间进程明显加快。然而，Arap1-/- 和野生型小鼠的基线 MAP 相似（102 ± 2 与 103 ± 2 mmHg；遥测测量；n = 10；P = 0.66）。注射脂多糖（LPS）（3 mg/kg）后，野生型小鼠中的 Arap1 表达逐渐下调，达到基线表达水平的 10% 以下。通过与促炎细胞因子（如肿瘤坏死因子 α 和干扰素 γ）一起孵育，可以在培养的系膜细胞中重现与内毒素血症相关的 Arap1 表达下降。与野生型小鼠相比，Arap1-/- 小鼠的血浆肾素浓度增加（66 ± 6 vs. 41 ± 4 ng AngI/ml/h；n = 23；P = 0.001），这可能有助于在基线条件下保留 MAP。与 +/+ 小鼠相比，Arap1-/- 小鼠的脉管系统对血管紧张素 II 的敏感性降低，如在离体灌注肾脏中所测定的。我们的数据表明，脓毒症期间 Arap1 表达下调会导致血管对血管紧张素 II 的敏感性降低，从而导致低血压的发生。
Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors, such as angiotensin II. The AT1 receptor-associated protein 1 (Arap1) is expressed in vascular smooth muscle cells and increases the surface expression of the AT1-receptor in vitro. We hypothesized that dysregulation of Arap1 may contribute to vascular hyporeactivity to angiotensin II during endotoxemia. Arap1-deficient mice were used to assess the role of Arap1 in sepsis-induced hypotension. The isolated perfused kidney was used as an in vitro model to determine the relevance of Arap1 for vascular resistance and sensitivity to angiotensin II. During endotoxemia, mean arterial blood pressure (MAP) decreased in both genotypes, with the time course of sepsis-induced hypotension being markedly accelerated in Arap1-/- compared to +/+ mice. However, baseline MAP was similar in Arap1-/- and wildtype mice (102 ± 2 vs.103 ± 2 mmHg; telemetry measurements; n = 10; P = 0.66). Following lipopolysaccharide (LPS) injections (3 mg/kg), Arap1 expression was successively down-regulated in the wildtype mice, reaching levels below 10% of baseline expression. The endotoxemia-related decline in Arap1 expression could be recapitulated in cultured mesangial cells by incubation with pro-inflammatory cytokines, such as tumor necrosis factor α and interferon γ. Plasma renin concentration was increased in Arap1-/- mice compared to wildtype mice (66 ± 6 vs. 41 ± 4 ng AngI/ml/h; n = 23; P = 0.001), presumably contributing to preserved MAP under baseline conditions. The sensitivity of the vasculature to angiotensin II was reduced in Arap1-/- compared to +/+ mice, as determined in the isolated perfused kidney. Our data suggest that down-regulation of Arap1 expression during sepsis contributes to the development of hypotension by causing reduced vascular sensitivity to angiotensin II.
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影响因子：
15.9
作者：
Castrop, H;Huang, YN;Schnermann, J
通讯作者：
Schnermann, J
DOI：
10.1016/j.bbrc.2003.09.154
发表时间：
2003-10-31
影响因子：
3.1
作者：
Guo, DF;Chenier, I;Inagami, T
通讯作者：
Inagami, T
影响因子：
3.3
作者：
Du, GW;Huang, P;Frohman, MA
通讯作者：
Frohman, MA
影响因子：
13.2
作者：
CUMMING, AD;DRIEDGER, AA;LINTON, AL
通讯作者：
LINTON, AL
影响因子：
3.1
作者：
van Eijk, LT;Nooteboom, A;Pickkers, P
通讯作者：
Pickkers, P