Pressure overload induces cardiac dysfunction and dilation in signal transducer and activator of transcription 6-deficient mice
Pressure overload induces cardiac dysfunction and dilation in signal transducer and activator of transcription 6-deficient mice
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DOI：
10.1161/01.cir.0000146798.70980.9a
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发表时间：
2004-10-26
期刊：
影响因子：
37.8
通讯作者：
Otsu, K
中科院分区：
文献类型：
--
作者：
Hikoso, S;Yamaguchi, O;Otsu, K
背景-信号转导子和转录激活子（STAT）蛋白构成介导许多细胞因子诱导的反应的转录因子家族。在肥厚的大鼠心脏和患有扩张型心肌病的人类心脏中，STAT6 被血管紧张素 II 激活。这提示STAT6可能参与心脏肥大和心力衰竭的发病机制。在本研究中，我们使用 STAT6 缺陷型 (STAT6(-/-)) 小鼠来检查 STAT6 的体内作用。方法和结果 - STAT6(-/-) 心脏未显示形态学、组织学或功能缺陷。我们在胸廓横主动脉缩窄 (TAC) 后 1 周检查了左心室结构和功能重塑。蛋白质印迹和免疫组织化学分析显示，TAC 后野生型小鼠心脏中 STAT6 活性增加。与野生型小鼠相比，STAT6(-/-)小鼠舒张末期左心室内部尺寸显着增加，并伴有收缩力受损，但肥厚参数没有差异。与野生型小鼠相比，TAC后STAT6(-/-)中末端脱氧核苷酸转移酶介导的生物素dUTP缺口末端标记阳性肌细胞的数量增加。在STAT6(-/-)心脏中观察到肿瘤坏死因子-α(TNF-α) mRNA的长时间诱导，而在野生型小鼠中TNF-α mRNA仅被短暂诱导。 Tristetraprolin 在 TAC 后在野生型小鼠中被诱导，但在 STAT6(-/-) 小鼠中则不然。使用分离的新生儿心肌细胞进行的 Tristetraprolin 报告基因检测表明，在野生型心肌细胞中内皮素-1 显着激活启动子，但在 STAT6(-/-) 心肌细胞中则不然。 STAT6(-/-)心肌细胞中内皮素-1启动子激活的缺失可通过强制表达STAT6来挽救。结论-STAT6对心脏血流动力学应激具有保护作用。
Background-Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6(-/-)) mice to examine the in vivo role of STAT6.Methods and Results-STAT6(-/-) hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6(-/-) mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling-positive myocytes after TAC had increased in STAT6(-/-) compared with wild-type mice. Prolonged induction of tumor necrosis factor-alpha (TNF-alpha) mRNA was observed in STAT6(-/-) hearts, whereas TNF-alpha mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6(-/-) mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6(-/-) cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6(-/-) cardiomyocytes was rescued by forced expression of STAT6.Conclusions-STAT6 plays a protective role against hemodynamic stress in hearts.