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 5

IL-33/ST2 signaling is cardioprotective in vivo.

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IL-33/ST2 signaling is cardioprotective in vivo. (A) Echocardiographic a...
(A) Echocardiographic analysis at 4 weeks after operation demonstrated increased left ventricular mass, left ventricular wall thickness, and reduced fractional shortening in ST2–/– mice. Treatment with IL-33 reduced hypertrophy only in WT mice. IL-33 caused no significant change under non-stress conditions in vivo. n = 10 (nonoperated control); 8 (WT sham); 10 (WT TAC); 8 (WT sham + IL-33); 10 (WT TAC + IL-33); 8 (ST2–/– sham); 12 (ST2–/– TAC); 8 (ST2–/– sham + IL-33); and 10 (ST2–/– TAC + IL-33). (B) Representative images and (C) quantitative analysis of mRNA expression of ANP and BNP relative to internal control (18S) in the left ventricle at 1 week after operation, as assessed by Northern analysis. White and black bars indicate sham-operated and TAC, respectively. (D) NF-κB activation from EMSA in vivo 1 week after operation. ANP and BNP expression and NF-κB activity increased in ST2–/– mice compared with WT mice; IL-33 reversed these changes only in WT mice. Positive and negative control mixtures as well as specific competition mixtures and supershift induce by p65 antibody are also shown. *P < 0.05 versus nonoperated control (A) or sham-operated WT (C); ΧP < 0.05 versus the same treatment in WT; †P < 0.05 versus sham in the same group; #P < 0.05.