IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system
Shoji Sanada, Daihiko Hakuno, Luke J. Higgins, Eric R. Schreiter, Andrew N.J. McKenzie, Richard T. Lee
Shoji Sanada, Daihiko Hakuno, Luke J. Higgins, Eric R. Schreiter, Andrew N.J. McKenzie, Richard T. Lee
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Research Article Cardiology

IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system

Abstract

ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II– and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-κB, it inhibited angiotensin II– and phenylephrine-induced phosphorylation of inhibitor of NF-κBα (IκBα) and NF-κB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2–/– mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2–/– littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.

Authors

Shoji Sanada, Daihiko Hakuno, Luke J. Higgins, Eric R. Schreiter, Andrew N.J. McKenzie, Richard T. Lee

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Figure 6

IL-33 improves survival after TAC and reduces TAC-induced macrophage infiltration, but does not inhibit apoptosis in vivo.

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IL-33 improves survival after TAC and reduces TAC-induced macrophage inf...
TAC was performed on WT and ST2–/– littermates. (A) Quantitative analysis of macrophages and TUNEL stain–positive nuclei. Computer-based image analysis was used. TAC increased macrophage infiltration after 1 week of operation. IL-33 alone did not induce macrophage infiltration in either WT or ST2–/– mice but co-treatment reduced macrophage infiltration after TAC only in WT mice. TAC approximately doubled the number of TUNEL-positive nuclei after 4 weeks in both WT and ST2–/– mice. IL-33 treatment did not affect TUNEL positivity. (B) Kaplan-Meier survival curve analysis revealed that the survival of ST2–/– mice under TAC was significantly reduced compared with that of WT mice. This experiment was blinded so that all procedures were performed without knowledge of mouse genotype. (C) Serial echocardiographic analysis of surviving mice revealed that ST2–/– mice had increased left ventricular mass and left ventricular wall thickness and reduced contractile function compared with WT mice. *P < 0.05 versus sham-operated WT (A) or baseline (C); ΧP < 0.05 versus the same treatment in WT; †P < 0.05 versus Sham in the same group; #P < 0.05.