IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension
IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension
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DOI：
10.1096/fj.10-174615
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Tsushima, Kensuke;Osawa, Tomoko;Nagai, Ryozo
高血压是一种典型的与现代生活方式相关的疾病，与心血管疾病的发生密切相关。血管紧张素II（ANG II）升高是高血压和心力衰竭的几个关键因素之一；然而，ANG II介导的发病机制仍知之甚少。在此，我们表明ANG II介导的心脏纤维化（而非肥大）受干扰素调节因子3（IRF3）调控，而此前IRF3仅在先天免疫系统中被研究。在ANG II灌注小鼠模型（3.0 mg/kg/d）中，我们将IRF3缺陷小鼠（Irf3(-/-)/Bcl2l12(-/-)）与匹配的野生型（WT）对照进行比较。心脏纤维化的发展[3.95 ± 0.62%（WT）对比1.41 ± 0.46%（Irf3(-/-)/Bcl2l12(-/-)）；P < 0.01]以及伴随的左心室舒张末期内径减小[2.89 ± 0.10 mm（WT）对比3.51 ± 0.15 mm（Irf3(-/-)/Bcl2l12(-/-)）；P = 0.012]在Irf3(-/-)/Bcl2l12(-/-)小鼠中受到强烈抑制，而肥大仍会发生。此外，我们提供了ANG II信号在小鼠心脏成纤维细胞中激活IRF3的证据。与先天免疫受体激活IRF3不同，ANG II激活IRF3的独特之处在于它是通过经典的ERK信号通路被激活的。因此，我们目前的研究揭示了IRF3在心脏重构中迄今未被认识的功能，为高血压诱导的心脏发病机制的进展提供了新的见解。 - 津岛（Tsushima）, K., 大泽（Osawa）, T., 柳井（Yanai）, H., 中岛（Nakajima）, A., 高冈（Takaoka）, A., 真锅（Manabe）, I., 大场（Ohba）, Y., 今井（Imai）, Y., 谷口（Taniguchi）, T., 永井（Nagai）, R. IRF3在血管紧张素II诱导的高血压期间调控小鼠的心脏纤维化而非肥大。《美国实验生物学会联合会杂志》（FASEB J.）25, 1531 - 1543（2011年）。www.fasebj.org
Hypertension is a typical modern lifestyle-related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II-mediated pathogenesis are still poorly understood. Here, we show that ANG II-mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II-infusion mouse model (3.0 mg/kg/d), we compared IRF3-deficient mice (Irf3(-/-)/Bcl2l12(-/-)) with matched wild-type (WT) controls. The development of cardiac fibrosis [3.95 +/- 0.62% (WT) vs. 1.41 +/- 0.46% (Irf3(-/-)/Bcl2l12(-/-)); P < 0.01] and accompanied reduction in left ventricle end-diastolic dimension [2.89 +/- 0.10 mm (WT) vs. 3.51 +/- 0.15 mm (Irf3(-/-)/Bcl2l12(-/-)); P=0.012] are strongly suppressed in Irf3(-/-)/Bcl2l12(-/-) mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension-induced cardiac pathogenesis.-Tsushima, K., Osawa, T., Yanai, H., Nakajima, A., Takaoka, A., Manabe, I., Ohba, Y., Imai, Y., Taniguchi, T., Nagai, R. IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension. FASEB J. 25, 1531-1543 (2011). www.fasebj.org