Abstract 416: IL-33 Reduces Cardiac Remodeling, Inhibits Myocardial Apoptosis and Improves Survival After Experimental Myocardial Infarction
ST2 is an IL-1 receptor family protein with membrane-bound (ST2L) and soluble (sST2; extracellular portion of ST2L) isoforms. We have previously reported that serum sST2 predicts mortality in myocardial infarction (MI) or heart failure in patients. Recently, a novel protein IL-33 was identified as the ligand for ST2. Since sST2 can bind IL-33, we hypothesized that IL-33 could be cardioprotective after experimental MI. In vitro studies with TUNEL staining, Western analysis for cleaved caspases-3 and DNA fragmentation analysis revealed that IL-33 potently reduces cardiomyocyte apoptosis induced by oxidative stress. Furthermore sST2 protein, a decoy receptor for IL-33, blocked the anti-apoptosis effect of IL-33. In vivo, we performed randomized and blinded studies in a total of 128 mice. Baseline echocardiography parameters 1 day after coronary ligation were comparable in each group. After 4 weeks, both ST2(−/ −) and wild type (WT) littermate mice had ventricular dilation with increased end-diastolic diameter and decreased fractional shortening (3.98+/−0.19mm and 36.6+/−3.4% in ST2(−/ −), 3.90+/−0.12mm and 38.3+/−2.9% in WT, n = 16 each) compared to Sham mice (2.88+/−0.04mm and 56.8+/−1.8% in ST2(−/ −), 2.85+/−0.04mm and 60.4+/−1.0% in WT, n = 8 each). Daily treatment with IL-33 (2μg i.p.) reduced ventricular dilation and restored contractile function in WT mice (3.46+/−0.15mm and 49.1+/−2.4%, p<0.05 each vs. no IL-33), but not in ST2(−/ −) mice (3.98+/−0.18mm, and 32.1+/−3.9%, p=NS each vs. no IL-33). Histological analysis demonstrated that cardiomyocyte apoptosis was reduced by IL-33 treatment in WT mice (20.6+/−4.2 vs. 35.2+/−4.5/105nuclei without IL-33, p<0.05), but was not in ST2(−/ −) mice (41.6+/−4.9 vs. 46.7+/−4.9/105nuclei without IL-33, p=NS). Furthermore, treatment with IL-33 improved 4-week survival after MI in WT mice (n=46, 57.1 to 83.3%, p<0.05), but not in ST2(−/ −) littermates (n=52, 57.1 to 54.2%, p=NS). In conclusion, IL-33 treatment after experimental MI reduces ventricular dilation, inhibits cardiomyocyte apoptosis and improves survival, and these benefits of IL-33 require ST2 signaling. These data suggest that IL-33 treatment could benefit patients after myocardial infarction, particularly those with high sST2 levels.