Interferon Regulatory Factor 9 Protects Against Cardiac Hypertrophy by Targeting Myocardin
Interferon Regulatory Factor 9 Protects Against Cardiac Hypertrophy by Targeting Myocardin
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干扰素调节因子 9 通过靶向心肌素预防心脏肥大
DOI：
10.1161/hypertensionaha.113.02083
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发表时间：
2014-01-01
期刊：
影响因子：
8.3
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Jiang, Ding-Sheng;Luo, Yu-Xuan;Li, Hongliang
病理性心肌肥厚是心力衰竭的主要危险因素。在这项研究中，我们确定了干扰素调节因子9（IRF 9），IRF家族的一员，作为一个以前未确定的心脏肥大的负调节。IRF9的表达水平在主动脉结扎诱导的心脏肥大动物的心脏中显著升高。IRF9缺陷小鼠在压力超负荷后表现出明显的心脏肥大，表现为心肌细胞大小增加、广泛的纤维化、心脏功能降低和肥大标志物表达增强，而心脏特异性过表达鼠IRF9的转基因小鼠表现出肥大反应的显著降低。从机制上讲，IRF9与p300竞争结合心肌蛋白的转录激活结构域，心肌蛋白是血清反应因子（SRF）的共激活因子。这种相互作用显著抑制心肌蛋白的转录活性，因为IRF9过表达强烈抑制心肌蛋白激活CArG盒依赖性报告基因的能力。这些结果提供了令人信服的证据，即IRF9通过抑制心脏中的心肌蛋白的转录活性来抑制心脏肥大的发展。
Pathological cardiac hypertrophy is a major risk factor for heart failure. In this study, we identified interferon regulatory factor 9 (IRF9), a member of the IRF family, as a previously unidentified negative regulator of cardiac hypertrophy. The level of IRF9 expression was remarkably elevated in the hearts from animals with aortic banding–induced cardiac hypertrophy. IRF9-deficient mice exhibited pronounced cardiac hypertrophy after pressure overload, as demonstrated by increased cardiomyocyte size, extensive fibrosis, reduced cardiac function, and enhanced expression of hypertrophy markers, whereas transgenic mice with cardiac-specific overexpression of murine IRF9 exhibited a significant reduction in the hypertrophic response. Mechanistically, IRF9 competes with p300 for binding to the transcription activation domain of myocardin, a coactivator of serum response factor (SRF). This interaction markedly suppresses the transcriptional activity of myocardin because IRF9 overexpression strongly inhibits the ability of myocardin to activate CArG box–dependent reporters. These results provide compelling evidence that IRF9 inhibits the development of cardiac hypertrophy by suppressing the transcriptional activity of myocardin in the heart.