巴特综合征/吉特曼综合征中的Rho激酶和纤溶酶原激活物抑制剂-1：与血管紧张素II信号传导的关系

Rho kinase and PAI-1 in Bartter's/Gitelman's syndromes: relationship to angiotensin II signaling.

作者信息

Pagnin Elisa, Davis Paul A, Sartori Michelangelo, Semplicini Andrea, Pessina Achille C, Calò Lorenzo A

机构信息

Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Italy.

出版信息

J Hypertens. 2004 Oct;22(10):1963-9. doi: 10.1097/00004872-200410000-00019.

DOI:10.1097/00004872-200410000-00019

PMID:15361768

Abstract

OBJECTIVE

Angiotensin II (Ang II)-mediated activation of Rho kinase (ROK) is involved in the pathophysiology of hypertension and cardiovascular remodeling. ROK also controls plasminogen activator inhibitor-1 (PAI-1) which promotes vascular fibrosis contributing to atherogenesis. Bartter's and Gitelman's syndromes (BS/GS) are useful models to investigate abnormalities of vascular tone regulation, due to their reduced short- and long-term signaling pathways of Ang II. This study evaluated, using BS/GS as a model, ROK and PAI-1 gene and protein expression and the effect of Ang II co-incubation on ROK and PAI-1 gene and protein expression.

DESIGN, METHODS AND RESULTS: We measured ROK and PAI-1 gene and protein expression [reverse transcription-polymerase chain reaction (RT-PCR) and Western blot] in mononuclear cells (PBM) from one BS and eight GS patients. The effect of Ang II on ROK and PAI-1 gene and protein expression was also evaluated and compared with 10 controls. ROK gene and protein expression was reduced in BS/GS [0.47 +/- 0.11 densitometric units (d.u.) versus 0.70 +/- 0.04 d.u., P = 0.0038 and 0.39 +/- 0.07 d.u. versus 0.55 +/- 0.07 d.u., P = 0.0026, respectively]. The basal level of PAI-1 gene and protein expression did not differ (0.40 +/- 0.03 d.u. versus 0.39 +/- 0.02 d.u. and 0.81 +/- 0.02 d.u. versus 0.83 +/- 0.02 d.u., respectively). Ang II increased ROK and PAI-1 gene and protein expression only in controls: from 0.70 +/- 0.04 to 0.90 +/- 0.06 d.u., P = 0.007 (ROK mRNA); from 0.55 +/- 0.07 to 0.86 +/- 0.07 d.u., P = 0.0005 (ROK protein); from 0.40 +/- 0.02 to 0.63 +/- 0.03 d.u., P = 0.001 (PAI-1 mRNA); and from 0.83 +/- 0.02 to 1.34 +/- 0.16 d.u., P = 0.0023 (PAI-1 protein).

CONCLUSIONS

This study confirms BS/GS as a human model to investigate interrelated systems involved in the pathophysiology of hypertension and throws more light on the cellular mechanisms of BS/GS reduced Ang II short- and long-term signaling pathways.

摘要

目的

血管紧张素II（Ang II）介导的Rho激酶（ROK）激活参与高血压和心血管重塑的病理生理学过程。ROK还调控纤溶酶原激活物抑制剂-1（PAI-1），PAI-1可促进血管纤维化，进而导致动脉粥样硬化。巴特综合征和吉特曼综合征（BS/GS）是研究血管张力调节异常的有用模型，因为它们的Ang II短期和长期信号通路减弱。本研究以BS/GS为模型，评估ROK和PAI-1基因及蛋白表达，以及Ang II共同孵育对ROK和PAI-1基因及蛋白表达的影响。

设计、方法与结果：我们检测了1例BS患者和8例GS患者外周血单核细胞（PBM）中ROK和PAI-1基因及蛋白表达[逆转录-聚合酶链反应（RT-PCR）和蛋白质印迹法]。还评估了Ang II对ROK和PAI-1基因及蛋白表达的影响，并与10例对照进行比较。BS/GS患者中ROK基因和蛋白表达降低[光密度单位（d.u.）分别为0.47±0.11 vs 0.70±0.04，P = 0.0038；0.39±0.07 vs 0.55±0.07，P = 0.0026]。PAI-1基因和蛋白表达的基础水平无差异（分别为0.40±0.03 d.u. vs 0.39±0.02 d.u.；0.81±0.02 d.u. vs 0.83±0.02 d.u.）。Ang II仅在对照组中增加ROK和PAI-1基因及蛋白表达：ROK mRNA从0.70±0.04增加到0.90±0.06 d.u.，P = 0.007；ROK蛋白从0.55±0.07增加到0.86±0.07 d.u.，P = 0.0005；PAI-1 mRNA从0.40±0.02增加到0.63±0.03 d.u.，P = 0.001；PAI-1蛋白从0.83±0.02增加到1.34±0.16 d.u.，P = 0.0023。