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The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB

We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective...

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Autores principales: Nguyen, Mai Tuyet, Lee, Min-Ah, Kim, Young-Kook, Kook, Hyun, Jeong, Dongtak, Jang, Seung Pil, Kwak, Tae Hwan, Park, Woo Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345366/
https://www.ncbi.nlm.nih.gov/pubmed/35917315
http://dx.doi.org/10.1371/journal.pone.0269735
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author Nguyen, Mai Tuyet
Lee, Min-Ah
Kim, Young-Kook
Kook, Hyun
Jeong, Dongtak
Jang, Seung Pil
Kwak, Tae Hwan
Park, Woo Jin
author_facet Nguyen, Mai Tuyet
Lee, Min-Ah
Kim, Young-Kook
Kook, Hyun
Jeong, Dongtak
Jang, Seung Pil
Kwak, Tae Hwan
Park, Woo Jin
author_sort Nguyen, Mai Tuyet
collection PubMed
description We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective apoptosis of MyoFBs. We first observed that the apoptotic protein p53 and the anti-apoptotic protein NFκB are simultaneously induced in MyoFBs. When the expression level of p53 was suppressed using a siRNA, CCN5 did not induce apoptosis in MyoFBs. By contrast, when NFκB signaling was inhibited using IKK VII, an IκB inhibitor, MyoFBs underwent apoptosis even in the absence of CCN5. SMAD7 is one of the downstream targets of CCN5 and it was previously shown to potentiate apoptosis in epithelial cells through inhibition of NFκB. In accordance with these reports, when the expression of SMAD7 was suppressed using a siRNA, NFκB signaling was enhanced, and CCN5 did not induce apoptosis. Lastly, we used a luciferase reporter construct to show that CCN5 positively regulated SMAD7 expression at the transcriptional level. Collectively, our data suggest that a delicate balance between the two mutually antagonistic proteins p53 and NFκB is maintained for MyoFBs to survive, and CCN5 tips the balance in favor of the apoptotic protein p53. This study provides insight into the anti-fibrotic activity of CCN5 during the regression of CF.
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spelling pubmed-93453662022-08-03 The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB Nguyen, Mai Tuyet Lee, Min-Ah Kim, Young-Kook Kook, Hyun Jeong, Dongtak Jang, Seung Pil Kwak, Tae Hwan Park, Woo Jin PLoS One Research Article We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective apoptosis of MyoFBs. We first observed that the apoptotic protein p53 and the anti-apoptotic protein NFκB are simultaneously induced in MyoFBs. When the expression level of p53 was suppressed using a siRNA, CCN5 did not induce apoptosis in MyoFBs. By contrast, when NFκB signaling was inhibited using IKK VII, an IκB inhibitor, MyoFBs underwent apoptosis even in the absence of CCN5. SMAD7 is one of the downstream targets of CCN5 and it was previously shown to potentiate apoptosis in epithelial cells through inhibition of NFκB. In accordance with these reports, when the expression of SMAD7 was suppressed using a siRNA, NFκB signaling was enhanced, and CCN5 did not induce apoptosis. Lastly, we used a luciferase reporter construct to show that CCN5 positively regulated SMAD7 expression at the transcriptional level. Collectively, our data suggest that a delicate balance between the two mutually antagonistic proteins p53 and NFκB is maintained for MyoFBs to survive, and CCN5 tips the balance in favor of the apoptotic protein p53. This study provides insight into the anti-fibrotic activity of CCN5 during the regression of CF. Public Library of Science 2022-08-02 /pmc/articles/PMC9345366/ /pubmed/35917315 http://dx.doi.org/10.1371/journal.pone.0269735 Text en © 2022 Nguyen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nguyen, Mai Tuyet
Lee, Min-Ah
Kim, Young-Kook
Kook, Hyun
Jeong, Dongtak
Jang, Seung Pil
Kwak, Tae Hwan
Park, Woo Jin
The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title_full The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title_fullStr The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title_full_unstemmed The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title_short The matricellular protein CCN5 induces apoptosis in myofibroblasts through SMAD7-mediated inhibition of NFκB
title_sort matricellular protein ccn5 induces apoptosis in myofibroblasts through smad7-mediated inhibition of nfκb
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345366/
https://www.ncbi.nlm.nih.gov/pubmed/35917315
http://dx.doi.org/10.1371/journal.pone.0269735
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