| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Local renin-angtotensin system is an important mediator for cardiomyocyte hypertrophy. We have shown that cardiotrophin-1(CT-1), a member of interleukin-6 family and one of the most potent inducer of cardiomyocyte hypertrophy, upregulates mRNA of angiotensinogen through JAK/STAT pathway stimulation in neonatal rat cultured ventricular myocytes. Atranscription factor, STAT3 homodimer activated by CT-1 binds to the St-domain, a STAT responsible element in the angiotensinogen gene promoter, and increases its promoter activity. Angiotensin II(AngII) type 1 receptor(AT1R) blocker(ARB) partially inhibits the CT-1-induced cardiomyocyte hypertrophy, without increase in AngII concentration in the medium from CT-1-stimulated cells. We performed further experiments to elucidate the mechanism of inhibition of CT-1-induced cardiomyocyte hypertrophy by ARB. ARB inhibited STAT3 tyrosine phosphorylation induced by CT-1 Abolishing AngII by combination treatment with angiotensin-converting enzyme inhibitor(ACEI), and antisense oligonucleotide for angiotensinogen, also decreased CT-1-induced STAT3 tyrosine-phosphorylation. Subthreshold concentration of AngII, which by itself did not activate STAT3, restored CT-1-inducea STAT3 activation in the cardiomyocytes treated with ACEI and antisense oligonucleotide. An association between AT1R, gp130(a receptor component for CT-1), and caveolin(a protein component in the caveolae) was found in a membrane fraction of cardiomyocytes. Filipin, which disperses caveolar domains, inhibited CT-1-induced STAT3 activation. These results suggested that the constitutive subthreshold signaling by AngII binding to AT1R provides a foundation for strong cellular response to CT-1 via supplying the binding site for STAT3. Importantly, the crosstalk of these hypertrophic signaling was served by caveolar membrane domain.
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