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NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase

Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression l...

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Autores principales: Park, Minsik, Choi, Seunghwan, Kim, Suji, Kim, Joohwan, Lee, Dong-Keon, Park, Wonjin, Kim, Taesam, Jung, Jiwon, Hwang, Jong Yun, Won, Moo-Ho, Ryoo, Sungwoo, Kang, Seung Goo, Ha, Kwon-Soo, Kwon, Young-Guen, Kim, Young-Myeong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376011/
https://www.ncbi.nlm.nih.gov/pubmed/30765689
http://dx.doi.org/10.1038/s12276-019-0212-8
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author Park, Minsik
Choi, Seunghwan
Kim, Suji
Kim, Joohwan
Lee, Dong-Keon
Park, Wonjin
Kim, Taesam
Jung, Jiwon
Hwang, Jong Yun
Won, Moo-Ho
Ryoo, Sungwoo
Kang, Seung Goo
Ha, Kwon-Soo
Kwon, Young-Guen
Kim, Young-Myeong
author_facet Park, Minsik
Choi, Seunghwan
Kim, Suji
Kim, Joohwan
Lee, Dong-Keon
Park, Wonjin
Kim, Taesam
Jung, Jiwon
Hwang, Jong Yun
Won, Moo-Ho
Ryoo, Sungwoo
Kang, Seung Goo
Ha, Kwon-Soo
Kwon, Young-Guen
Kim, Young-Myeong
author_sort Park, Minsik
collection PubMed
description Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression levels of microRNA-155 (miR-155) in cultured VSMCs, mouse vessels, and clinical specimens and then assessed its role in VSMC function. Treatment with tumor necrosis factor-α (TNF-α) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-κB inhibition. MiR-155 expression was also increased in high-fat diet-fed ApoE(−/−) mice and in patients with atherosclerosis and preeclampsia. The miR-155 levels were inversely correlated with soluble guanylyl cyclase β1 (sGCβ1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGCβ1 transcript. TNF-α-induced miR-155 caused VSMC phenotypic switching, which was confirmed by the downregulation of VSMC-specific marker genes, suppression of cell proliferation and migration, alterations in cell morphology, and NO-induced vasorelaxation. These events were mitigated by miR-155 inhibition. Moreover, TNF-α did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155(−/−) mice. These findings suggest that NF-κB-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGCβ1 expression. These data suggest that NF-κB-responsive miR-155 is a novel negative regulator of VSMC functions by impairing the sGC/cGMP pathway, which is essential for maintaining the VSMC contractile phenotype and vasorelaxation, offering a new therapeutic target for the treatment of atherosclerosis and preeclampsia.
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spelling pubmed-63760112019-02-25 NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase Park, Minsik Choi, Seunghwan Kim, Suji Kim, Joohwan Lee, Dong-Keon Park, Wonjin Kim, Taesam Jung, Jiwon Hwang, Jong Yun Won, Moo-Ho Ryoo, Sungwoo Kang, Seung Goo Ha, Kwon-Soo Kwon, Young-Guen Kim, Young-Myeong Exp Mol Med Article Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression levels of microRNA-155 (miR-155) in cultured VSMCs, mouse vessels, and clinical specimens and then assessed its role in VSMC function. Treatment with tumor necrosis factor-α (TNF-α) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-κB inhibition. MiR-155 expression was also increased in high-fat diet-fed ApoE(−/−) mice and in patients with atherosclerosis and preeclampsia. The miR-155 levels were inversely correlated with soluble guanylyl cyclase β1 (sGCβ1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGCβ1 transcript. TNF-α-induced miR-155 caused VSMC phenotypic switching, which was confirmed by the downregulation of VSMC-specific marker genes, suppression of cell proliferation and migration, alterations in cell morphology, and NO-induced vasorelaxation. These events were mitigated by miR-155 inhibition. Moreover, TNF-α did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155(−/−) mice. These findings suggest that NF-κB-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGCβ1 expression. These data suggest that NF-κB-responsive miR-155 is a novel negative regulator of VSMC functions by impairing the sGC/cGMP pathway, which is essential for maintaining the VSMC contractile phenotype and vasorelaxation, offering a new therapeutic target for the treatment of atherosclerosis and preeclampsia. Nature Publishing Group UK 2019-02-15 /pmc/articles/PMC6376011/ /pubmed/30765689 http://dx.doi.org/10.1038/s12276-019-0212-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Park, Minsik
Choi, Seunghwan
Kim, Suji
Kim, Joohwan
Lee, Dong-Keon
Park, Wonjin
Kim, Taesam
Jung, Jiwon
Hwang, Jong Yun
Won, Moo-Ho
Ryoo, Sungwoo
Kang, Seung Goo
Ha, Kwon-Soo
Kwon, Young-Guen
Kim, Young-Myeong
NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title_full NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title_fullStr NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title_full_unstemmed NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title_short NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
title_sort nf-κb-responsive mir-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376011/
https://www.ncbi.nlm.nih.gov/pubmed/30765689
http://dx.doi.org/10.1038/s12276-019-0212-8
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