Myocardial infarction (MI), a severe form of coronary heart disease, is the leading cause of death and hospitalization worldwide. Adverse remodeling of the left ventricle after MI can induce heart failure and a poor prognosis due to excessive improper repair. Therefore, the balance of scar formation and debris clearance is of extremely importance to avoid rupture post MI, and it is necessary to investigate a viable technique to accelerate wound healing while avoiding excessive repair and fibrosis formation.

Chitinase 3-like 1 (Chil1/mice, Chi3l1/YKL-40/human), a member of the chitinase-like protein family, is related to tissue repair and remodeling response and involved in cardiovascular diseases such as heart failure and atrial fibrillation [1]. However, some questions are unsolved such as the following: What’s the actual role of Chil1 on cardiac wound healing? Whether chil1 promotes wound healing and heart repair post-MI?

In this issue of Journal of Cardiovascular Translational Research, Ye and colleagues performed a series of complete and rigorous experiments to investigate the function of Chil1 and ingeniously unveiled the mechanism of its regulation in cardiac repair post MI. In order to investigate the alteration of Chil1 post MI, the authors extracted macrophage and neutrophils from ischemic heart tissue, complemented with bone marrow-derived macrophages model, to assess the Chil1 level. Different from the previous study [2], a reduced expression of Chil1 was found in the injured area overall post-MI, which was secreted by neutrophils and reparative macrophages. To explain the difference, a supplementary mechanism was proposed by Ye and colleagues by which the loss of endothelial and muscle cells leading to a reduction of Chil1 with a supplementary secretion from macrophages and neutrophils. Based on this finding, Ye and colleagues further utilized a specific-overexpressed AAV9 strategy to overexpress Chil1 in MI model and ultimately conduced assessments including infarct size, Masson staining, echocardiography, and picrosirius red-staining. Compared with MI mice, Chil1 overexpressed mice presented a thicker wall and a reduced collagen volume in the infarct zone at day28 post MI.

The protective effect of Chil1 in MI-induced cardiac adverse modeling was proved by treating cells with an artificially synthesized recombinant Chil1 protein (rChil1). Ye and colleagues creatively synthesized rChil1 and used it to treat adult mice-derived cardiac fibroblast (amCF). Cell viability experiment and Ki67 immunostaining showed an increased amCF proliferation, and collagen-related gene expression (Col1, Col3, α-SMA, and Postn protein) was induced by rChil1 treatment. Using global phosphor-proteomics analysis, gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and IPA, Ye and colleges identified the downstream pathway of Chil1 in mice with the MI mutation, namely, ErbB signaling as well as its downstream (RAF/MEK1/ERK signaling pathway). To verify this hypothesis, Ye and colleagues performed functional blocking experiment via using dabrafenib, an inhibitor of RAF, and then treated with rChil1 in amCF. Suppression of RAF by dabrafenib significantly reduced the ratios of p-RAF/RAF, p-MEK1/MEK1, and p-ERK/ ERK, indicating that RAF/MEK1/ERK signaling mediated the effect of Chil1. Interestingly, the authors did not observe an alteration of myocardial angiogenesis and cardiomyocyte apoptosis in Chil1-overexpressed MI mice, demonstrating that Chil1-induced cardioprotection operates in an angiogenesis/cardiomyocyte apoptosis-independent manner. More evidence was further obtained by survival rata, cardiac function, and collagen deposition analysis. RAF inhibitor, at least partly, attenuated the wound healing capacity improved by Chil1 in MI modeling [3].

Together, this work identified Chil1 as a novel protective target for cardiac benign remodeling through direct binding to EGFR and subsequent activation of the downstream RAF/MEK1/ERK signaling pathway, suggesting a promising therapeutical strategy for activating fibroblast and improving cardiac function after MI.