The growth factor meteorin-like and its receptor KIT in heart failure

About This Grant

PROJECT SUMMARY Heart failure (HF) is a prevalent healthcare concern associated with unacceptably high mortality rates and significant decreases in quality of life. Chronic inflammation contributes to HF pathogenesis; however, the precise role of the immune response during disease is not fully understood. Acute pressure overload, imposed in the mouse by transverse aortic constriction surgery (TAC), evokes a strong local inflammatory response. Signals emitted from stressed cardiomyocytes trigger the inflammatory cascade and cardiac expression of proinflammatory cytokines and chemokines increases. While most immune-targeting therapies have shown attenuating effects on HF after TAC, depletion of macrophages promoted functional decline, suggesting there may also be beneficial effects from the inflammatory response. One macrophage-derived cytokine that might have favorable effects during HF is meteorin-like (METRNL). METRNL is secreted by myeloid cells and was shown by our group to have a proangiogenic effect after myocardial infarction by binding to the KIT receptor on endothelial cells (ECs). The interaction between METRNL-producing inflammatory cells and KIT+ ECs is a prime example of the importance of paracrine communication in tissue repair after heart injury and opens up a new therapeutic approach. Considering that myeloid cells swiftly accumulate in the pressure-overloaded myocardium and may release protective factors, and that myocardial angiogenesis helps preserve heart function during persistent afterload stress, we hypothesize myeloid cell-derived METRNL may play an important, adaptive role in this context. This proposal aims to investigate the beneficial aspects of inflammation in HF by defining, specifically, the role of METRNL and its receptor, KIT, after pressure-overload. We want to determine if METRNL is involved in the pathogenesis of HF and assess its use as a therapy for disease amelioration. Our preliminary work supports that METRNL attenuates pressure overload-induced HF. Metrnl and Kit transcriptional expression increase significantly following TAC, and Metrnl-deficient mice have reduced survival and heart function after TAC. Our preliminary data show that patients with severe aortic stenosis have elevated METRNL plasma concentrations, indicating pressure overload also triggers METRNL release in humans. We will use genetic gain- and loss-of-function approaches to study the role of myeloid cell-derived METRNL and its receptor KIT in the pressure-overloaded heart. Our goal is to elucidate the role of METRNL in regulating HF progression (Aim 1), to define the major cell types producing and targeted by METRNL (Aim 2), and to assess METRNL’s therapeutic potential in HF (Aim 3). Successful completion of these aims will shed light on the role of crosstalk between the immune system and heart tissue during HF, and evaluate potential protein and gene transfer-based therapeutic approaches for attenuating disease progression. Our work plan and the state-of-the-art research environment emphasize technical and nontechnical training in skills that are highly relevant in contemporary cardiovascular research. The envisioned training will efficiently prepare me for a career as an independent scientist.