Abstract
Cytokine-like 1 (Cytl1) is a secreted protein that is involved in diverse biological processes. A comparative modeling study indicated that Cytl1 is structurally and functionally similar to monocyte chemoattractant protein 1 (MCP-1). As MCP-1 plays an important role in cardiac fibrosis (CF) and heart failure (HF), we investigated the role of Cytl1 in a mouse model of CF and HF. Cytl1 was upregulated in the failing mouse heart. Pressure overload-induced CF was significantly attenuated in cytl1 knock-out (KO) mice compared to that from wild-type (WT) mice. By contrast, adeno-associated virus (AAV)-mediated overexpression of cytl1 alone led to the development of CF in vivo. The endothelial-mesenchymal transition (EndMT) and the transdifferentiation of fibroblasts (FBs) to myofibroblasts (MFBs) have been suggested to contribute considerably to CF. Adenovirus-mediated overexpression of cytl1 was sufficient to induce these two critical CF-related processes in vitro, which were completely abrogated by co-treatment with SB-431542, an antagonist of TGF-β receptor 1. Cytl1 induced the expression of TGF-β2 both in vivo and in vitro. Antagonizing the receptor for MCP-1, C-C chemokine receptor type 2 (CCR2), with CAS 445479-97-0 did not block the pro-fibrotic activity of Cytl1 in vitro. Collectively, our data suggest that Cytl1 plays an essential role in CF likely through activating the TGF-β-SMAD signaling pathway. Although the receptor for Cyt1l remains to be identified, Cytl1 provides a novel platform for the development of anti-CF therapies.
MeSH terms
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Animals
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Aorta / surgery
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Benzamides / pharmacology
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Cell Transdifferentiation / drug effects
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Constriction, Pathologic / surgery
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Dioxoles / pharmacology
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Disease Models, Animal
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Endomyocardial Fibrosis / genetics
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Endomyocardial Fibrosis / metabolism*
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Endomyocardial Fibrosis / pathology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression Regulation
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Heart Failure / genetics
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Heart Failure / metabolism*
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Heart Failure / pathology
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Humans
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Male
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Mice
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Mice, Knockout
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Myocardial Infarction / genetics
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Myocardial Infarction / metabolism*
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Myocardial Infarction / pathology
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Myocardial Reperfusion Injury / genetics
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Myocardial Reperfusion Injury / metabolism*
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Myocardial Reperfusion Injury / pathology
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Myofibroblasts / drug effects
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Myofibroblasts / metabolism
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Myofibroblasts / pathology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, CCR2 / genetics
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Receptors, CCR2 / metabolism
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Receptors, Cytokine / genetics
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Receptors, Cytokine / metabolism*
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction
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Smad Proteins / genetics
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Smad Proteins / metabolism*
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Transforming Growth Factor beta2 / genetics
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Transforming Growth Factor beta2 / metabolism*
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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Ccr2 protein, mouse
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Dioxoles
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Receptors, CCR2
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Receptors, Cytokine
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Tgfb2 protein, mouse
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Transforming Growth Factor beta2
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cytokine-like factor-1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
Grants and funding
This work was supported by the Bio & Medical Technology Development Program (2015M3A9E6028951) and the Basic Research Laboratory Program (2016R1A4A1009895) of NRF funded by the Korean government and a grant from the Systems Biology Infrastructure Establishment Grant provided by GIST. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.