Abstract 1380: IL-33/ST2 is a Critical Cardioprotective Fibroblast-cardiomyocyte Signaling System Activated by Mechanical Overload
ST2 is a member of the IL-1 receptor family with a transmembrane (ST2L) isoform as well as a soluble (sST2) isoform that has the ligand binding domain but no intracellular signaling domain. sST2 is robustly induced by mechanical stress in cardiomyocytes, and serum sST2 predicts outcome in patients with heart failure. Recently, a novel protein called IL-33 was identified as a functional ligand of ST2L. Therefore, we tested how IL-33/ST2 signaling regulates cardiomyocytes (CMs) and cardiac fibroblasts (CFs) both in vitro and in vivo. Gene expression of IL-33 and sST2 was >5 fold greater in CFs than CMs, and mechanical strain increased IL-33 gene expression by 135+/−36% in CFs and 92+/−21% in CMs (p<0.05). In CMs, IL33 (up to 100ng/ml) induced CM amino acid uptake by 30+/−9% (p<0.05) but markedly antagonized angiotensin-II (Ang-II; 0.1μM) and phenylephrine (Phe; 50μM)-induced leucine uptake (all p<0.05). sST2 blunted the effects of IL-33, indicating that sST2 functions as a soluble receptor decoy. IL-33 did not affect ERK/p38/JNK or Akt activation by Ang-II, but reduced both Ang-II-induced and Phe-induced NF-κB activation in CMs (n=5, p<0.05 each). In vivo, following transaortic constriction (TAC), ST2(−/ −) mice had increased left ventricular hypertrophy, more dilation, and reduced fractional shortening (n=10 in each group, p<0.05 each) as well as worse survival (n=53, p<0.05) than WT littermates. Histological analysis showed more cardiac fibrosis and cardiomyocyte hypertrophy in ST2(−/ −) mice than in WT littermates (n=23, p<0.05 each) after TAC. Furthermore, daily treatment with recombinant IL-33 (2μg i.p.) reduced fibrosis and hypertrophy after TAC in WT mice (n=10, p<0.05) but not in ST2(−/ −) littermates with TAC (n=10). In conclusion, IL-33/ST2 signaling is a novel cardioprotective fibroblast/cardiomyocyte communication system activated by mechanical stimuli in vitro and in vivo. Furthermore, these data suggest that IL-33 may have therapeutic potential for inhibiting cardiac fibrosis.