|Budget Amount *help
¥39,000,000 (Direct Cost : ¥39,000,000)
Fiscal Year 1997 : ¥17,500,000 (Direct Cost : ¥17,500,000)
Fiscal Year 1996 : ¥21,500,000 (Direct Cost : ¥21,500,000)
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.