Published Online
on September 22, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Interleukin-33 Prevents Apoptosis and Improves Survival After Experimental Myocardial Infarction through ST2 Signaling

Kenjiro Seki; Shoji Sanada; Anastacia Yurievna Kudinova; Matthew L. Steinhauser; Vandna Handa; Joseph Gannon and Richard T. Lee¹

Brigham and Women's Hospital and Harvard Medical School, Boston, MA

^* Corresponding author; email: rlee{at}partners.org

Background—ST2 is an interleukin-1 receptor family member with membrane-bound (ST2L) and soluble (sST2) isoforms, and, sST2 is a biomarker for poor outcome in patients with myocardial infarction (MI). IL-33, the recently-discovered ligand for ST2, activates NF-kB and thus may regulate apoptotic cell death. We tested the hypothesis that IL-33 is cardioprotective after MI through ST2 signaling.

Methods and Results—IL-33 protected cultured cardiomyocytes from hypoxia- induced apoptosis, and this cardioprotection was partially inhibited by sST2. IL-33 induced expression of the anti-apoptotic factors XIAP, cIAP1 and survivin. To define the cardioprotective role of IL-33 in vivo, we performed a blinded and randomized study of ischemia/reperfusion in rats. IL-33 reduced cardiomyocyte apoptosis, suppressed caspase-3 activity and increased expression of IAP family member proteins. IL-33 decreased both infarct and fibrosis volumes at 15 days; furthermore, both echocardiographic and hemodynamic studies revealed that IL-33 improved ventricular function. To determine if cardioprotection by IL-33 is mediated through ST2 signaling, a randomized and blinded study of ST2-/- vs. wild type (WT) littermate mice was performed in 98 mice subjected to MI. At 4 weeks following MI, IL-33 reduced ventricular dilation and improved contractile function in WT mice, but not in ST2-/- mice. Finally, IL-33 improved survival after MI in WT, but not in ST2-/- mice.

Conclusion—IL-33 prevents cardiomyocyte apoptosis and improves cardiac function and survival after MI through ST2 signaling.

Key Words: apoptosis • myocardial infarction • Cytokine