Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress

作者：Veeraveedu Punniyakoti T^*; Sanada Shoji^*; Okuda Keiji; Fu Hai Ying; Matsuzaki Takashr; Araki Ryo; Yamato Masaki; Yasuda Koubun; Sakata Yasushi; Yoshimoto Tomohiro; Minamino Tetsuo

来源：Biochemical Pharmacology, 2017, 138: 73-80.

DOI：10.1016/j.bcp.2017.04.022

• IL-33
• Cardiac remodeling
• Hypertrophy
• Fibrosis
• TAC

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.

• 出版日期2017-8-15