Mederle Katharina, Schweda Frank, Kattler Veronika, Doblinger Elisabeth, Miyata Keishi, Höcherl Klaus, Oike Yuichi, Castrop Hayo
Crit Care. 2013 Jul 11;17(4):R130. doi: 10.1186/cc12809.
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.
脓毒症患者的低血压是由血容量不足、血管舒张以及对血管收缩剂（如血管紧张素II）反应性降低所致。1型血管紧张素II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1型血管紧张素II受体的表面表达。我们推测，Arap1失调可能在内毒素血症期间导致血管对血管紧张素II反应性降低。
使用Arap1基因敲除小鼠评估Arap1在脓毒症诱导的低血压中的作用。将离体灌注肾用作体外模型，以确定Arap1与血管阻力及对血管紧张素II敏感性之间的相关性。
在内毒素血症期间，两种基因型小鼠的平均动脉血压（MAP）均下降，与野生型小鼠相比，Arap1基因敲除小鼠脓毒症诱导的低血压病程明显加快。然而，Arap1基因敲除小鼠和野生型小鼠的基线MAP相似（遥测测量；分别为102±2 mmHg和103±2 mmHg；n = 10；P = 0.66）。注射脂多糖（LPS，3 mg/kg）后，野生型小鼠中Arap1表达相继下调，降至低于基线表达的10%。通过与促炎细胞因子（如肿瘤坏死因子α和干扰素γ）孵育，可在培养的系膜细胞中重现内毒素血症相关的Arap1表达下降。与野生型小鼠相比，Arap1基因敲除小鼠的血浆肾素浓度升高（分别为66±6和41±4 ng血管紧张素I/ml/h；n = 23；P = 0.001），这可能是基线条件下MAP得以维持的原因。如在离体灌注肾中所测定，与野生型小鼠相比，Arap1基因敲除小鼠的血管对血管紧张素II的敏感性降低。
我们的数据表明，脓毒症期间Arap1表达下调通过降低血管对血管紧张素II的敏感性，导致低血压的发生。
