Affiliations 

  • 1 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Pharmaceutical Chemistry, International Medical University, Kuala Lumpur 57000, Malaysia. Electronic address: nspkoti2001@gmail.com
  • 2 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Electronic address: s-sanada@cardiology.med.osaka-u.ac.jp
  • 3 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  • 4 Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
  • 5 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
Biochem Pharmacol, 2017 Aug 15;138:73-80.
PMID: 28450225 DOI: 10.1016/j.bcp.2017.04.022

Abstract

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-α 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.