Interleukin 13 Promotes Cardiomyocyte Proliferation and Heart Regeneration In Vivo

Abstract

AimsPreliminary data shows that the cytokine interleukin 13 (IL13) can promote neonatal mouse cardiomyocyte (CM) proliferation in vitro. From this, we hypothesize that IL13 and its downstream signaling pathway(s) play a role in stimulating mammalian heart cell cycle activity in vivo. We aim to test the role of endogenous, and exogenously administered, IL13 in promoting cardiomyocyte cell cycle activity and heart regeneration in vivo.Methods and ResultsTo understand if IL13 could promote CM proliferation in vivo, we collected whole hearts from C57/BL6J and IL13−/− neonatal mice. Heart halves were saved for histology and immunohistochemistry (IHC) and ventricle pieces for RNA extraction and protein lysates. To measure proliferation, we sectioned neonatal hearts for IHC and stained them with Proliferating Cell Nuclear Antigen (PCNA) or Phosphorylated Histone H3 (pH3). To ensure the proliferating cells were CM specific, we dual‐stained PCNA with Myocyte Enhancer Factor 2C (Mef2C) and pH3 with Cardiac Troponin T2 (cTnnt). We found CMs in IL13−/− mice show a decrease in PCNA when compared to BL6 wildtype CMs, indicative of decreased proliferation in the absence of IL13. When analyzed by qRT‐PCR, our IL13−/− mice also showed an increase in hypertrophic markers, specifically Brain Natriuretic peptide (nppb). Nppb is primarily expressed by the heart ventricles upon myocardial stretch and is shown to be upregulated during heart failure. Additionally, we found that by administering recombinant IL13 (rIL13) to the IL13−/− mice, we were able to rescue some of these phenotypes, namely increasing PCNA‐ and pH3‐positive CMs and decreasing nppb expression. To elucidate the downstream signaling pathways of IL13, we treated cultured neonatal rat CMs with rIL13 or no treatment. We preformed western blot and RNAsequencing on these CMs treated with rIL13 and both of these methods indicated a strong initial activation of Erk1/2 and Akt signaling pathways.ConclusionsOur data suggests that endogenous and exogenously administered IL13 can promote CM cell cycle activity. IL13−/− mice show decreased levels of CM proliferation, which was in part rescued when administered rIL13. We also found that rIL13 treatment in CMs activates Erk1/2 and Akt pathways, which have been shown to be pro‐proliferative and pro‐survival in CMs, respectively. In the future, IL13 and its corresponding signaling pathways could potentially be targeted to promote pro‐regenerative therapies in cardiac tissue.Support or Funding InformationAmerican Heart AssociationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.