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Constitutive Subthreshold Signal by Local Renin-Angiotensin System Facilitates the Cardiotrophin-1-Induced Strong Activation of JAK/STAT Signaling Pathway and Cardiomyocyte Hypertrophy

局部肾素-血管紧张素系统的组成性阈下信号促进心肌营养蛋白-1 诱导的 JAK/STAT 信号通路和心肌细胞肥大的强烈激活

基本信息

批准号：
14570629
负责人：
FUKUZAWA Jun
金额：
$ 2.3万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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.

局部肾素-血管紧张素系统是心肌细胞肥大的重要介质。我们发现，白细胞介素-6家族成员、心肌细胞肥厚最有效的诱导剂之一心营养因子-1（CT-1）通过JAK/STAT通路刺激新生大鼠培养的心室肌细胞上调血管紧张素原mRNA。转录因子STAT3同二聚体被CT-1激活，结合到st结构域，血管紧张素原基因启动子中的STAT负责元件，并增加其启动子活性。血管紧张素II(AngII) 1型受体（AT1R）阻滞剂（ARB）部分抑制ct -1诱导的心肌细胞肥大，而不增加ct -1刺激细胞培养基中的AngII浓度。我们进行了进一步的实验来阐明ARB抑制ct -1诱导的心肌细胞肥大的机制。ARB可抑制CT-1联合血管紧张素转换酶抑制剂（ACEI）和血管紧张素原反义寡核苷酸诱导的STAT3酪氨酸磷酸化，也可降低CT-1诱导的STAT3酪氨酸磷酸化。在ACEI和反义寡核苷酸处理的心肌细胞中，亚阈浓度的AngII本身不激活STAT3，但恢复了ct -1诱导的STAT3激活。在心肌细胞的膜部分中发现了AT1R、gp130（CT-1的受体成分）和小窝蛋白（小窝中的蛋白质成分）之间的关联。分散空泡结构域的Filipin抑制了ct -1诱导的STAT3激活。这些结果表明，AngII结合AT1R的构成性阈下信号通过提供STAT3的结合位点，为细胞对CT-1的强烈反应提供了基础。重要的是，这些肥厚信号的串扰是由腔泡膜结构域提供的。