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

细胞因子在心力衰竭的发病机制和病理生理机制中的作用日益受到重视。在我们的脑心肌炎病毒性心肌炎所致充血性心力衰竭小鼠模型中，白介素1β、白介素2、肿瘤坏死因子和干扰素的信使RNA的表达在急性期增加，但在病毒接种后持续很长时间。我们还研究了Dahl盐敏感(DS)大鼠左室肥厚和随后出现心力衰竭迹象的细胞因子的表达。用定量逆转录聚合酶链式反应检测DS大鼠左室IL-1βmRNA含量，发现DS大鼠左室肥厚时IL-1βm RNA含量增加，CHF时较同龄Dahl耐盐(DR)大鼠进一步升高。在DS大鼠心肌梗死后1周，IL-1β、IL-6和TNF-α基因表达达高峰，随后在梗死区迅速下降。相反，在梗死后20周，这些细胞因子的基因表达水平在非梗死区仍显著高于梗死区。此外，这些细胞因子在非梗死区的水平与慢性期测量的左心室舒张末内径相关。随着我们对细胞因子在心力衰竭中的病理生理学和致病作用有更多的了解，应该有可能设计出更好和更有针对性的药物。

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.