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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2024 |
| Country: | España |
| Institution: | Universidad Francisco de Vitoria |
| Repository: | DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria |
| Language: | English |
| OAI Identifier: | oai:ddfv.ufv.es:10641/5517 |
| Online Access: | https://hdl.handle.net/10641/5517 |
| Access Level: | Open access |
| Keyword: | Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA |
| _version_ | 1878734589500850176 |
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| author | Ramírez Carracedo, Rafael |
| 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 |
| author_browse | Alcharani, Nunzio Botana Veguillas, Laura González-Cucharero, Claudia Hernández Navarro, Ignacio Javier Díez-Mata Jiménez-Guirado, Beatriz Moreno-Gómez-Toledano, Rafael Ramírez Carracedo, Rafael Saura, Marta Tesoro Santos, Laura Zamorano, Jose Luis Zaragoza Sánchez, Carlos |
| 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 |
| collection | DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_6c8aa9602deb977458583e9a57cda3aa |
| institution | Universidad Francisco de Vitoria |
| instname_str | Universidad Francisco de Vitoria |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddfv.ufv.es:10641/5517 |
| publishDate | 2024 |
| publishDateSort | 2024 |
| publisher | Lippincott, Williams & Wilkins |
| publisherStr | Lippincott, Williams & Wilkins |
| reponame_str | DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria |
| 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, 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 Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA 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. Lippincott, Williams & Wilkins https://hdl.handle.net/10641/5517 |
| 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 | 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_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_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. |
| topic | Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA |
| topic_facet | Atherosclerosis Extracellular Matrix MetalloPRotease INducer microRNA |
| url | https://hdl.handle.net/10641/5517 |