Published online before print September 22, 2009, doi: 10.1161/CIRCHEARTFAILURE.109.873240
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Original Articles |
Interleukin-33 Prevents Apoptosis and Improves Survival After Experimental Myocardial Infarction Through ST2 Signaling
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Richard T. Lee, MD, Partners Research Facility, Room 280, 65 Landsdowne Street, Cambridge, MA 02139. E-mail rlee{at}partners.org
Received April 21, 2009; accepted July 27, 2009.
Background— ST2 is an interleukin (IL)-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 nuclear factor 
B 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 antiapoptotic 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 whether cardioprotection by IL-33 is mediated through ST2 signaling, a randomized and blinded study of ST2–/– versus wild-type littermate mice was performed in 98 mice subjected to MI. At 4 weeks after MI, IL-33 reduced ventricular dilation and improved contractile function in wild-type mice but not in ST2–/– mice. Finally, IL-33 improved survival after MI in wild-type but not in ST2–/– mice.
Conclusion— IL-33 prevents cardiomyocyte apoptosis and improves cardiac function and survival after MI through ST2 signaling.
Key Words: myocardial infarction • cytokine • apoptosis