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

被引:304
作者
Seki, Kenjiro [1 ]
Sanada, Shoji [1 ]
Kudinova, Anastacia Y. [1 ]
Steinhauser, Matthew L. [1 ]
Handa, Vandna [1 ]
Gannon, Joseph [1 ]
Lee, Richard T. [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Med, Cardiovasc Div,Brigham & Womens Hosp, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
myocardial infarction; cytokine; apoptosis; FAMILY-MEMBER ST2; REPERFUSION INJURY; ISCHEMIA/REPERFUSION INJURY; IL-33; HEART; RECEPTOR; CARDIOMYOPATHY; ATTENUATION; INHIBITION; MORTALITY;
D O I
10.1161/CIRCHEARTFAILURE.109.873240
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 kappa 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. (Circ Heart Fail. 2009; 2: 684-691.)
引用
收藏
页码:684 / U211
页数:16
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