Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress
Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress
复制标题
DOI：
10.1016/j.bcp.2017.04.022
复制
发表时间：
2017-08-15
影响因子：
5.8
通讯作者：
Minamino, Tetsuo
中科院分区：
文献类型：
--
作者：
Veeraveedu, Punniyakoti T.;Sanada, Shoji;Minamino, Tetsuo
背景与目的：ST 2是白细胞介素1（IL-1）受体家族成员之一，包括膜结合型（ST 2L）和可溶性型（sST 2）。临床试验表明，血清sST 2水平可预测心肌梗死或慢性心力衰竭（HF）患者的预后。同时，我们和其他人报道了ST 2消融在缺血性和非缺血性HF中引起了过度的心脏重构。在这里，我们测试了是否IL-33，ST 2的配体，保护心肌对HF诱导的机械过载使用配体特异性敲除（IL-33（-/-））mimes.Methods和结果：在IL-33和WT-同窝出生的小鼠进行了横向主动脉缩窄（TAC）/假手术。在研究期间，频繁进行超声心动图测量。收获心脏用于RNA和组织学测量。在TAC造成机械负荷后，IL-33（-/-）小鼠心肌Th 1细胞因子（如TNF-α）的mRNA表达比WT小鼠增强。8周后，IL-33（-/-）小鼠与WT同窝小鼠相比，左心室肥大加重，心室扩张增加，缩短率降低，纤维化加重，炎症和存活率降低。相应地，心肌肥厚（c-Myc/BNP）分子标志物的mRNA表达也显着增强IL-33（-/-）小鼠比WT mice.Conclusions：我们报告的第一次，消融IL-33直接和显着导致心脏重塑加剧受损的心脏功能和生存机械应力。这些数据突出了IL-33/ST 2系统在应激心肌中的心脏保护作用，并揭示了IL-33在非缺血性HF中的潜在治疗作用。(C)2017爱思唯尔公司All rights reserved.
Background and purpose: ST2 is one of the interleukin (IL)-1 receptor family members comprising of membrane-bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non-ischemic HF. Here, we tested whether IL-33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL-33(-/-)) mice.Methods and results: Transverse aortic constriction (TAC)/sham surgery were carried out in both IL-33 and WT-littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF-alpha were enhanced in IL-33(-/-) mice than in WT mice. After 8-weeks, IL-33 (-/-) mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c-Myc/BNP) molecular markers were also significantly enhanced in IL-33(-/-) mice than those in WT mice.Conclusions: We report for the first time that ablation of IL-33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL-33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL-33 in non-ischemic HF. (C) 2017 Elsevier Inc. All rights reserved.