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BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway

Objectives: Calcific aortic valve disease (CAVD) is most common in the aging population and is without effective medical treatments. Brain and muscle ARNT-like 1 (BMAL1) is related to calcification. It has unique tissue-specific characteristics and plays different roles in different tissues’ calcifi...

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Autores principales: Jiang, Yefan, Wang, Song, Lin, Wenfeng, Gu, Jiaxi, Li, Geng, Shao, Yongfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054744/
https://www.ncbi.nlm.nih.gov/pubmed/36975874
http://dx.doi.org/10.3390/jcdd10030110
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author Jiang, Yefan
Wang, Song
Lin, Wenfeng
Gu, Jiaxi
Li, Geng
Shao, Yongfeng
author_facet Jiang, Yefan
Wang, Song
Lin, Wenfeng
Gu, Jiaxi
Li, Geng
Shao, Yongfeng
author_sort Jiang, Yefan
collection PubMed
description Objectives: Calcific aortic valve disease (CAVD) is most common in the aging population and is without effective medical treatments. Brain and muscle ARNT-like 1 (BMAL1) is related to calcification. It has unique tissue-specific characteristics and plays different roles in different tissues’ calcification processes. The purpose of the present study is to explore the role of BMAL1 in CAVD. Methods: The protein levels of BMAL1 in normal and calcified human aortic valves and valvular interstitial cells (VICs) isolated from normal and calcified human aortic valves were checked. HVICs were cultured in osteogenic medium as an in vitro model, and BMAL1 expression and location were detected. TGF-β and RhoA/ROCK inhibitors and RhoA-siRNA were applied to detect the mechanism underlying the source of BMAL1 during HVICs’ osteogenic differentiation. ChIP was applied to check whether BMAL1 could directly interact with the runx2 primer CPG region, and the expression of key proteins involved in the TNF signaling pathway and NF-κ B pathway was tested after silencing BMAL1. Results: In this study, we found that BMAL1 expression was elevated in calcified human aortic valves and VICs isolated from calcified human aortic valves. Osteogenic medium could promote BMAL1 expression in HVICs and the knockdown of BMAL1 induced the inhibition of HVICs’ osteogenic differentiation. Furthermore, the osteogenic medium promoting BMAL1 expression could be blocked by TGF-β and RhoA/ROCK inhibitors and RhoA-siRNA. Meanwhile, BMAL1 could not bind with the runx2 primer CPG region directly, but knockdown of BMAL1 led to decreased levels of P-AKT, P-IκBα, P-p65 and P-JNK. Conclusions: Osteogenic medium could promote BMAL1 expression in HVICs through the TGF-β/RhoA/ROCK pathway. BMAL1 could not act as a transcription factor, but functioned through the NF-κ B/AKT/MAPK pathway to regulate the osteogenic differentiation of HVICs.
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spelling pubmed-100547442023-03-30 BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway Jiang, Yefan Wang, Song Lin, Wenfeng Gu, Jiaxi Li, Geng Shao, Yongfeng J Cardiovasc Dev Dis Article Objectives: Calcific aortic valve disease (CAVD) is most common in the aging population and is without effective medical treatments. Brain and muscle ARNT-like 1 (BMAL1) is related to calcification. It has unique tissue-specific characteristics and plays different roles in different tissues’ calcification processes. The purpose of the present study is to explore the role of BMAL1 in CAVD. Methods: The protein levels of BMAL1 in normal and calcified human aortic valves and valvular interstitial cells (VICs) isolated from normal and calcified human aortic valves were checked. HVICs were cultured in osteogenic medium as an in vitro model, and BMAL1 expression and location were detected. TGF-β and RhoA/ROCK inhibitors and RhoA-siRNA were applied to detect the mechanism underlying the source of BMAL1 during HVICs’ osteogenic differentiation. ChIP was applied to check whether BMAL1 could directly interact with the runx2 primer CPG region, and the expression of key proteins involved in the TNF signaling pathway and NF-κ B pathway was tested after silencing BMAL1. Results: In this study, we found that BMAL1 expression was elevated in calcified human aortic valves and VICs isolated from calcified human aortic valves. Osteogenic medium could promote BMAL1 expression in HVICs and the knockdown of BMAL1 induced the inhibition of HVICs’ osteogenic differentiation. Furthermore, the osteogenic medium promoting BMAL1 expression could be blocked by TGF-β and RhoA/ROCK inhibitors and RhoA-siRNA. Meanwhile, BMAL1 could not bind with the runx2 primer CPG region directly, but knockdown of BMAL1 led to decreased levels of P-AKT, P-IκBα, P-p65 and P-JNK. Conclusions: Osteogenic medium could promote BMAL1 expression in HVICs through the TGF-β/RhoA/ROCK pathway. BMAL1 could not act as a transcription factor, but functioned through the NF-κ B/AKT/MAPK pathway to regulate the osteogenic differentiation of HVICs. MDPI 2023-03-06 /pmc/articles/PMC10054744/ /pubmed/36975874 http://dx.doi.org/10.3390/jcdd10030110 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jiang, Yefan
Wang, Song
Lin, Wenfeng
Gu, Jiaxi
Li, Geng
Shao, Yongfeng
BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title_full BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title_fullStr BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title_full_unstemmed BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title_short BMAL1 Promotes Valvular Interstitial Cells’ Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway
title_sort bmal1 promotes valvular interstitial cells’ osteogenic differentiation through nf-κ b/akt/mapk pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054744/
https://www.ncbi.nlm.nih.gov/pubmed/36975874
http://dx.doi.org/10.3390/jcdd10030110
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