Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy.
Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy.
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干扰素调节因子 7 作为病理性心脏肥大的新型负调节因子发挥作用。
DOI：
10.1161/hypertensionaha.113.02653
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Li H
中科院分区：
文献类型：
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作者：
Jiang DS;Liu Y;Zhou H;Zhang Y;Zhang XD;Zhang XF;Chen K;Gao L;Peng J;Gong H;Chen Y;Yang Q;Liu PP;Fan GC;Zou Y;Li H
心肌肥厚是一个复杂的病理过程，涉及炎症和细胞凋亡等多种因素。干扰素调节因子7（IRF 7）是一种多功能调节因子，参与免疫调节、细胞分化、凋亡和肿瘤发生。然而，IRF 7在心脏肥大中的作用仍不清楚。我们在心脏特异性IRF 7转基因小鼠、IRF 7敲除小鼠和这些小鼠的野生型同窝仔中进行了主动脉结扎。我们的研究结果表明，IRF 7在主动脉缩窄诱导的动物心脏和心肌细胞中下调，这些心肌细胞用血管紧张素II或苯肾上腺素处理48小时。因此，心脏特异性过表达的IRF 7显着减弱压力超负荷诱导的心脏肥大，纤维化和功能障碍，而IRF 7的损失导致相反的效果。此外，IRF 7在体外保护血管紧张素II诱导的心肌细胞肥大。从机制上讲，我们确定IRF 7依赖性心脏保护作用是通过IRF 7与κB激酶-β抑制剂结合，随后核因子-κB失活介导的。事实上，用心脏特异性抑制剂κBα S32 A/S36 A超阻遏物转基因阻断核因子-κB信号传导抵消了IRF 7缺陷的不利影响。相反，通过κB激酶-β S177 E/S181 E（组成型活性）转基因的心脏特异性条件性抑制剂激活核因子-κB信号传导，否定了IRF 7过表达的抗肥大作用。我们的数据表明IRF 7通过抑制核因子-κB信号通路作为病理性心脏肥大的一种新的负性调节剂，并且可能构成病理性心脏肥大的潜在治疗靶点。
Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBαS32A/S36A super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-βS177E/S181E (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy.