Cytokine-Like 1 Regulates Cardiac Fibrosis via Modulation of TGF-β Signaling.
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.
College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Jooyeon
J
Kim
College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Jihwa
J
Kim
College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Seung Hee
SH
Lee
The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York 10029, United States of America.
Sacha V
SV
Kepreotis
The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York 10029, United States of America.
Jimeen
J
Yoo
College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Jang-Soo
JS
Chun
The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York 10029, United States of America.
Roger J
RJ
Hajjar
The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York 10029, United States of America.
Dongtak
D
Jeong
College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Woo Jin
WJ
Park
D000818:Animals; D001011:Aorta / Q000601:surgery; D001549:Benzamides / Q000494:pharmacology; D054338:Cell Transdifferentiation / Q000187:drug effects; D003251:Constriction, Pathologic / Q000601:surgery; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C515335:Ccr2 protein, mouse; D004149:Dioxoles; D054390:Receptors, CCR2; D018121:Receptors, Cytokine; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; C113554:cytokine-like factor-1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I