NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

Ramírez Carracedo, Rafael; Hernández Navarro, Ignacio; Moreno-Gómez-Toledano, Rafael; Javier Díez-Mata; Tesoro Santos, Laura; González-Cucharero, Claudia; Jiménez-Guirado, Beatriz; Alcharani, Nunzio; Botana Veguillas, Laura; Saura, Marta; Zamorano, Jose Luis; Zaragoza Sánchez, Carlos

NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

Background: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. Methods: C57BL/6 mice lack...

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Autores:	Ramírez Carracedo, Rafael, Hernández Navarro, Ignacio, Moreno-Gómez-Toledano, Rafael, Javier Díez-Mata, Tesoro Santos, Laura, González-Cucharero, Claudia, Jiménez-Guirado, Beatriz, Alcharani, Nunzio, Botana Veguillas, Laura, Saura, Marta, Zamorano, Jose Luis, Zaragoza Sánchez, Carlos
Tipo de recurso:	artículo
Fecha de publicación:	2024
País:	España
Institución:	Universidad Francisco de Vitoria
Repositorio:	DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
Idioma:	inglés
OAI Identifier:	oai:ddfv.ufv.es:10641/5517
Acceso en línea:	https://hdl.handle.net/10641/5517
Access Level:	acceso abierto
Palabra clave:	Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA

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spelling	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.Ramírez Carracedo, RafaelHernández Navarro, IgnacioMoreno-Gómez-Toledano, RafaelJavier Díez-MataTesoro Santos, LauraGonzález-Cucharero, ClaudiaJiménez-Guirado, BeatrizAlcharani, NunzioBotana Veguillas, LauraSaura, MartaZamorano, Jose LuisZaragoza Sánchez, CarlosAtherosclerosisExtracellular Matrix MetalloPRotease INducermicroRNABackground: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. Methods: C57BL/6 mice lacking ApoE, NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal–Wallis tests were performed to determine statistical differences. Results: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3-deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. Conclusion: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.Lippincott, Williams & Wilkins20242024-01-0120242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10641/5517reponame:DDFV. Repositorio Institucional de la Universidad Francisco de Vitoriainstname:Universidad Francisco de VitoriaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddfv.ufv.es:10641/55172026-06-11T12:44:57Z
dc.title.none.fl_str_mv	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
title	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
spellingShingle	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis. Ramírez Carracedo, Rafael Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA
title_short	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
title_full	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
title_fullStr	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
title_full_unstemmed	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
title_sort	NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.
dc.creator.none.fl_str_mv	Ramírez Carracedo, Rafael Hernández Navarro, Ignacio Moreno-Gómez-Toledano, Rafael Javier Díez-Mata Tesoro Santos, Laura González-Cucharero, Claudia Jiménez-Guirado, Beatriz Alcharani, Nunzio Botana Veguillas, Laura Saura, Marta Zamorano, Jose Luis Zaragoza Sánchez, Carlos
author	Ramírez Carracedo, Rafael
author_facet	Ramírez Carracedo, Rafael Hernández Navarro, Ignacio Moreno-Gómez-Toledano, Rafael Javier Díez-Mata Tesoro Santos, Laura González-Cucharero, Claudia Jiménez-Guirado, Beatriz Alcharani, Nunzio Botana Veguillas, Laura Saura, Marta Zamorano, Jose Luis Zaragoza Sánchez, Carlos
author_role	author
author2	Hernández Navarro, Ignacio Moreno-Gómez-Toledano, Rafael Javier Díez-Mata Tesoro Santos, Laura González-Cucharero, Claudia Jiménez-Guirado, Beatriz Alcharani, Nunzio Botana Veguillas, Laura Saura, Marta Zamorano, Jose Luis Zaragoza Sánchez, Carlos
author2_role	author author author author author author author author author author author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv	Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA
topic	Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA
description	Background: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. Methods: C57BL/6 mice lacking ApoE, NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal–Wallis tests were performed to determine statistical differences. Results: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3-deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. Conclusion: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.
publishDate	2024
dc.date.none.fl_str_mv	2024 2024-01-01 2024 2024-01-01
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/10641/5517
url	https://hdl.handle.net/10641/5517
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Lippincott, Williams & Wilkins
publisher.none.fl_str_mv	Lippincott, Williams & Wilkins
dc.source.none.fl_str_mv	reponame:DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria instname:Universidad Francisco de Vitoria
instname_str	Universidad Francisco de Vitoria
reponame_str	DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
collection	DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,811543

NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

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