Activation and functional significance of the renin- angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor
Activation and functional significance of the renin- angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor
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DOI：
10.1161/01.cir.0000081768.13378.bf
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发表时间：
2003-08-05
期刊：
影响因子：
37.8
通讯作者：
Mann, DL
中科院分区：
文献类型：
--
作者：
Flesch, M;Höper, A;Mann, DL
背景-肾素-血管紧张素系统(RAS)和肿瘤坏死因子(TNF)之间的交叉调节在非心肌细胞类型中的功能意义已经建立；然而，RAS和TNF之间相互作用的程度和功能意义尚未在心脏中得到表征。方法和结果-我们在一株心脏限制性过表达肿瘤坏死因子的转基因小鼠(MHCsTNF)中检测了RAS组分的表达。当在4、8和12周龄时进行检查时，MHCsTNF小鼠的心肌RAS活性增加，表现为ACE mRNA水平和ACE活性的增加以及血管紧张素II多肽水平的增加。此外，MHCsTNF小鼠的心肌血管紧张素受体基因和蛋白水平降低，与受体的同源脱敏一致。然而，与对照组相比，MHCsTNF小鼠的肾素和血管紧张素原的表达并没有增加。为了确定RAS激活在MHCsTNF小鼠中的功能意义，我们用血管紧张素I受体拮抗剂氯沙坦(30 mg/kg)或稀释剂从4-8周龄处理小鼠。核磁共振心动图分析显示，氯沙坦治疗后左室重量和室壁厚度恢复正常。结论Ras与肿瘤坏死因子在心脏功能上存在显著的相互作用，这些相互作用在左心室重构的发生发展过程中起重要作用。
Background-The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart.Methods and Results-We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis.Conclusions-Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.