Interferon Regulatory Factor 1 Is Required for Cardiac Remodeling in Response to Pressure Overload
Interferon Regulatory Factor 1 Is Required for Cardiac Remodeling in Response to Pressure Overload
复制标题
压力超负荷时心脏重塑需要干扰素调节因子 1。
DOI：
10.1161/hypertensionaha.114.03229
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发表时间：
2014-07-01
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;Li, Liangpeng;Li, Hongliang
干扰素调节因子1(IRF1)是IRF家族中的一个重要成员，先前被证明与免疫系统相关，并参与细胞凋亡和肿瘤抑制。然而，IRF1在压力超负荷诱导的心脏重构中的作用尚不清楚。利用遗传学方法，我们在体内和体外确定了IRF1转录因子在心脏重构调节中的核心作用，并确定了这一过程的机制。在衰竭的人类心脏和肥大的小鼠心脏中，IRF1的表达水平都发生了显著的变化。心脏特异性IRF1过表达的转基因小鼠加重了主动脉缩窄引起的心肌肥大、心室扩张、纤维化和功能障碍，而IRF1缺陷(基因敲除)小鼠的肥大反应显著降低。在全球IRF1基因敲除大鼠模型中也观察到了类似的结果。从机制上讲，IRF1对病理刺激的促肥大效应与诱导型一氧化氮合酶(INOS)的直接激活有关。此外，我们还在iNOS基因的启动子区域确定了1个IRF1结合位点，这是其转录所必需的。为了在体内检测IRF1-iNOS轴，我们产生了IRF1转基因/iNOS基因敲除小鼠。IRF1对这些小鼠产生了深远的有害影响；然而，这些影响被iNOS消融所抵消。这些数据表明，IRF1-iNOS轴是心脏重构的重要调节因子，IRF1可能是心脏重构的有效治疗靶点。
Interferon regulatory factor 1 (IRF1), a critical member of the IRF family, was previously shown to be associated with the immune system and to be involved in apoptosis and tumor suppression. However, the role of IRF1 in pressure overload-induced cardiac remodeling has remained unclear. Using genetic approaches, we established a central role for the IRF1 transcription factor in the regulation of cardiac remodeling both in vivo and in vitro, and we determined the mechanism underlying this process. The expression level of IRF1 was remarkably altered in both failing human hearts and hypertrophic murine hearts. Transgenic mice with cardiac-specific IRF1 overexpression exacerbated aortic banding-induced cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, whereas IRF1-deficient (knockout) mice exhibited a significant reduction in the hypertrophic response. Similar results were observed in a global IRF1-knockout rat model. Mechanistically, the prohypertrophic effects elicited by IRF1 in response to pathological stimuli were associated with the direct activation of inducible nitric oxide synthase (iNOS). Furthermore, we identified 1 IRF1-binding site in the promoter region of the iNOS gene, which was essential for its transcription. To examine the IRF1-iNOS axis in vivo, we generated IRF1-transgenic/iNOS-knockout mice. IRF1 exerted profoundly detrimental effects in these mice; however, these effects were nullified by iNOS ablation. These data suggest the IRF1-iNOS axis as a crucial regulator of cardiac remodeling and that IRF1 could be a potent therapeutic target for cardiac remodeling.