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缺乏两种激肽受体的小鼠血压正常,且可免受内毒素诱导的低血压影响。

Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension.

作者信息

Cayla Cécile, Todiras Mihail, Iliescu Radu, Saul Vera V, Gross Volkmar, Pilz Bernhard, Chai Guixuan, Merino Vanessa F, Pesquero João B, Baltatu Ovidiu C, Bader Michael

机构信息

Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin-Buch, Germany.

出版信息

FASEB J. 2007 Jun;21(8):1689-98. doi: 10.1096/fj.06-7175com. Epub 2007 Feb 8.

Abstract

Kinins play a central role in the modulation of cardiovascular function and in the pathophysiology of inflammation. These peptides mediate their effects by binding to two specific G-protein coupled receptors named B1 and B2. To evaluate the full functional relevance of the kallikrein-kinin system, we generated mice lacking both kinin receptors (B1B2-/-). Because of the close chromosomal position of both kinin receptor genes, B1B2-/- mice could not be obtained by simple breeding of the single knockout lines. Therefore, we inactivated the B1 receptor gene by homologous recombination in embryonic stem cells derived from B2-deficient animals. The B1B2-/- mice exhibited undetectable levels of mRNAs for both receptors and a lack of response to bradykinin (B2 agonist) and des-Arg9-bradykinin (B1 agonist), as attested by contractility studies with isolated smooth muscle tissues. B1B2-/- mice are healthy and fertile, and no sign of cardiac abnormality was detected. They are normotensive but exhibit a lower heart rate than controls. Furthermore, kinin receptor deficiency affects the pathogenesis of endotoxin-induced hypotension. While blood pressure decreased markedly in wild-type mice and B2-/- and moderately in B1-/- mice after bacterial lipopolysaccharide (LPS) injection, blood pressure remained unchanged in B1B2-/- mice. These results clearly demonstrate a pivotal role of kinins and their receptors in hypotension induced by endotoxemia in mice.

摘要

激肽在心血管功能调节和炎症病理生理学中发挥核心作用。这些肽通过与两种特定的G蛋白偶联受体B1和B2结合来介导其作用。为了评估激肽释放酶-激肽系统的全部功能相关性,我们培育出了缺乏两种激肽受体的小鼠(B1B2-/-)。由于两种激肽受体基因在染色体上位置相近,无法通过简单杂交单个基因敲除品系获得B1B2-/-小鼠。因此,我们通过同源重组在源自B2缺陷动物的胚胎干细胞中使B1受体基因失活。B1B2-/-小鼠两种受体的mRNA水平均检测不到,并且对缓激肽(B2激动剂)和去-Arg9-缓激肽(B1激动剂)无反应,这通过对分离的平滑肌组织的收缩性研究得到证实。B1B2-/-小鼠健康且可育,未检测到心脏异常迹象。它们血压正常,但心率低于对照组。此外,激肽受体缺陷影响内毒素诱导的低血压的发病机制。细菌脂多糖(LPS)注射后,野生型小鼠和B2-/-小鼠血压明显下降,B1-/-小鼠血压中度下降,而B1B2-/-小鼠血压保持不变。这些结果清楚地证明了激肽及其受体在小鼠内毒素血症诱导的低血压中起关键作用。

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