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Analysis of signal transduction among cells in the pathogenesis of heart failure and its application for the diagnosis and treatment

心力衰竭发病机制中细胞间信号转导分析及其在诊治中的应用

基本信息

批准号：
08407018
负责人：
SASAYAMA Shigetake
金额：
$ 24.96万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo.In our murine model of congestive heart failure resulting from encephalomyocarditis virus myocarditis, expression of messenger RNAs of interleukin (IL)-1beta, IL-2, TNF-alpha and interferon gamma increased in the acute stage, but persisted long after virus inoculation.We also investigated cytokine expression in Dahl salt-sensitive (DS) rats that developed hypertrophy of the left ventricle and subsequently showed signs of heart failure, and in a rat model of ischemic heart failure. The IL-1beta mRNA content of the LV of DS rats determined by quantitatibe reverse-transcriptase polymerase chain reaction was increased when LV hypertrophy developed, and further increased at the CHF stage compared with that of age-matched Dahl salt-resistant (DR) rats. In DS rats, the number of interstitial macrophages increased, and most of the IL-1beta immunoreactivity was localized in those macrophages throughout the LV.In rat model of myocardial infarction, IL-1beta, IL-6 and TNF-alpha gene expressions peaked at 1 week after infarction and decreased rapidly thereafter in the infarcted region. In contrast, at 20 weeks after infarction, the gene expression levels of these cytokines remained significantly higher in the noninfarcted than in the infarcted zone. Furthermore, the levels of these cytokines in the noninfarcted region correlated with the LV end-diastolic diameter measured in the chronic stage.As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents.

人们越来越认识到细胞因子是心力衰竭发病机制和病理生理学的重要因素。据报道，心力衰竭患者的循环细胞因子水平升高，并且多种细胞因子已被证明可以在体外和体内抑制心肌收缩力。在我们的脑心肌炎病毒性心肌炎引起的充血性心力衰竭小鼠模型中，白细胞介素（IL）-1β、IL-2、TNF-α和干扰素γ的信使RNA表达增加我们还研究了达尔盐敏感（DS）大鼠的细胞因子表达，这些大鼠出现左心室肥大并随后表现出心力衰竭的迹象，以及缺血性心力衰竭的大鼠模型。定量逆转录酶聚合酶链式反应测定DS大鼠左心室IL-1β mRNA含量随左心室肥厚而增加，与同龄Dahl耐盐(DR)大鼠相比，在CHF阶段进一步增加。在 DS 大鼠中，间质巨噬细胞数量增加，大部分 IL-1β 免疫反应性位于整个左室的巨噬细胞中。在心肌梗死大鼠模型中，IL-1β、IL-6 和 TNF-α 基因表达在梗死后 1 周达到峰值，此后在梗死区域迅速下降。相反，在梗塞后20周，这些细胞因子的基因表达水平在非梗塞区仍然显着高于梗塞区。此外，非梗塞区域中这些细胞因子的水平与慢性阶段测量的左心室舒张末期直径相关。随着我们对细胞因子在心力衰竭中的病理生理和发病作用的了解更多，应该有可能设计出更好、更有针对性的药物制剂。