Walther Thomas, Klostermann Katrin, Heringer-Walther Silvia, Schultheiss Heinz-Peter, Tschöpe Carsten, Stepan Holger
Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany.
Regul Pept. 2003 Nov 15;116(1-3):95-100. doi: 10.1016/j.regpep.2003.07.003.
Since first reports demonstrated interactions between the natriuretic peptide (NPS) and renin-angiotensin system (RAS), our experiments should clarify whether cardiac brain natriuretic peptide (BNP) is regulated in mice genetically altered for components of the RAS.
The study was carried out in hypotensive AT1- and angiotensinogen (ANG)-, and normotensive AT2-knockout mice, and in hypertensive animals overexpressing ANG and wildtype controls of each genotype. Ventricular BNP expression was analyzed by RNase-protection assay (RPA) (n=6). Cardiac fibrosis was visualized by Sirius red staining. While ANG overexpression increases cardiac BNP-mRNA expression (1035+/-210 vs. wildtype: 405+/-95 in PSL/mm(2), P<0.01), its deficiency had no influence. Both AT1- and AT2-knockouts showed significantly decreased BNP-mRNA concentrations (AT1: 21+/-6 vs. wildtype: 139+/-28 in PSL/mm(2), P<0.001; AT2: 8+/-2 vs. 19+/-3 in PSL/mm(2), P<0.05). These alterations correlate to reduced cardiac fibrosis in AT2-deficient animals, and an unchanged matrix content in ANG knockouts.
Increased BNP-mRNA levels in hypertensive ANG-overexpressing mice and decreased BNP in hypotensive AT1-deficient animals suggest that this mRNA expression is blood pressure-dependent. However, the observed alterations of fibrosis and the unchanged BNP in hypotensive ANG knockouts and impaired BNP-mRNA expression in normotensive AT2-deficient mice demonstrate a direct interaction of the RAS and NPS that is fibrosis- rather than blood pressure-dependent.
自从最初的报告证明利钠肽（NPS）与肾素 - 血管紧张素系统（RAS）之间存在相互作用以来，我们的实验旨在阐明在RAS组分基因改变的小鼠中，心脏脑钠肽（BNP）是否受到调节。
该研究在低血压的AT1和血管紧张素原（ANG）基因敲除小鼠、正常血压的AT2基因敲除小鼠，以及每种基因型过表达ANG的高血压动物和野生型对照中进行。通过核糖核酸酶保护分析（RPA）（n = 6）分析心室BNP表达。用天狼星红染色观察心脏纤维化。虽然ANG过表达增加心脏BNP - mRNA表达（PSL/mm²中为1035±210 vs野生型：405±95，P < 0.01），但其缺乏则无影响。AT1和AT2基因敲除均显示BNP - mRNA浓度显著降低（AT1：PSL/mm²中为21±6 vs野生型：139±28，P < 0.001；AT2：PSL/mm²中为8±2 vs 19±3，P < 0.05）。这些改变与AT2缺陷动物中减少的心脏纤维化以及ANG基因敲除中不变的基质含量相关。
高血压ANG过表达小鼠中BNP - mRNA水平升高以及低血压AT1缺陷动物中BNP降低表明这种mRNA表达是血压依赖性的。然而，在低血压ANG基因敲除中观察到的纤维化改变和不变的BNP以及正常血压AT2缺陷小鼠中受损的BNP - mRNA表达证明了RAS和NPS之间存在直接相互作用，这种相互作用是纤维化依赖性而非血压依赖性的。
