Ana Purroy1, Carmen Roncal2, Josune Orbe2, Olivier Meilhac3, Miriam Belzunce1, Guillermo Zalba4, Ricardo Villa-Bellosta5, Vicente Andrés6, William C Parks7, José A Páramo8, José A Rodríguez9. 1. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. 2. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain. 3. INSERM UMR698, AP-HP, Department of Neurology, Bichat Stroke Center, University Paris Diderot, Sorbonne Paris Cité, Paris, F-75018, France. 4. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain. 5. Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spain. 6. CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spain. 7. Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 8. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; Hematology Service, Clínica Universidad de Navarra, Pamplona, Spain. 9. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: josean@unav.es.
Abstract
BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis and vascular calcification. Among them, we reported that MMP10 is present in human atheroma, associated with atherosclerosis. However, it remains unclear whether MMP10 is involved in atherogenesis and vascular calcification. METHODS: MMP10 was measured in serum from patients with subclinical atherosclerosis and analyzed in carotid endarterectomies by immunostaining. ApoE-deficient mice (Apoe-/-) were crossed to MMP10-deficient (Mmp10-/-) mice and followed up to 20 months. Plaque area and composition were assessed by histology and immunohistochemistry. Inflammatory markers were measured in atherosclerotic plaques by RT-qPCR, and leukocyte subpopulations were analyzed by flow cytometry. In vitro calcification assays were performed in aortic vascular smooth muscle cells (VSMC). RESULTS: MMP10 serum levels were associated with coronary calcification in subjects with subclinical atherosclerosis. Immunostaining revealed MMP10 expression in human atheromas, spatially associated with calcification areas, and complicated plaques released higher amounts of MMP10 than non-diseased segments. Interestingly, vascular MMP10 expression was confined to the atherosclerotic lesion in Apoe-/- mice, and Apoe-/-Mmp10-/- showed a substantial reduction in atherosclerotic lesion size, macrophage content and plaque calcification. Reduced local and systemic inflammatory markers could be demonstrated in Apoe-/-Mmp10-/- by gene expression and flow cytometry analysis. Calcium phosphate deposition and vascular calcification markers were downregulated in VSMC from Apoe-/-Mmp10-/- mice. CONCLUSIONS: Delayed plaque progression and altered cellular composition in the absence of MMP10 suggests that MMP10 plays a role in atherosclerosis, favoring inflammation, development and complication of the plaque.
BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis and vascular calcification. Among them, we reported that MMP10 is present in human atheroma, associated with atherosclerosis. However, it remains unclear whether MMP10 is involved in atherogenesis and vascular calcification. METHODS: MMP10 was measured in serum from patients with subclinical atherosclerosis and analyzed in carotid endarterectomies by immunostaining. ApoE-deficient mice (Apoe-/-) were crossed to MMP10-deficient (Mmp10-/-) mice and followed up to 20 months. Plaque area and composition were assessed by histology and immunohistochemistry. Inflammatory markers were measured in atherosclerotic plaques by RT-qPCR, and leukocyte subpopulations were analyzed by flow cytometry. In vitro calcification assays were performed in aortic vascular smooth muscle cells (VSMC). RESULTS: MMP10 serum levels were associated with coronary calcification in subjects with subclinical atherosclerosis. Immunostaining revealed MMP10 expression in human atheromas, spatially associated with calcification areas, and complicated plaques released higher amounts of MMP10 than non-diseased segments. Interestingly, vascular MMP10 expression was confined to the atherosclerotic lesion in Apoe-/- mice, and Apoe-/-Mmp10-/- showed a substantial reduction in atherosclerotic lesion size, macrophage content and plaque calcification. Reduced local and systemic inflammatory markers could be demonstrated in Apoe-/-Mmp10-/- by gene expression and flow cytometry analysis. Calcium phosphate deposition and vascular calcification markers were downregulated in VSMC from Apoe-/-Mmp10-/- mice. CONCLUSIONS: Delayed plaque progression and altered cellular composition in the absence of MMP10 suggests that MMP10 plays a role in atherosclerosis, favoring inflammation, development and complication of the plaque.
Authors: María Marcos-Jubilar; Josune Orbe; Carmen Roncal; Florencio J D Machado; José Antonio Rodriguez; Alejandro Fernández-Montero; Inmaculada Colina; Raquel Rodil; Juan C Pastrana; José A Páramo Journal: Life (Basel) Date: 2021-05-01
Authors: Manuel Navarro-Oviedo; Roberto Muñoz-Arrondo; Beatriz Zandio; Juan Marta-Enguita; Anna Bonaterra-Pastra; Jose Antonio Rodríguez; Carmen Roncal; Jose A Páramo; Estefania Toledo; Joan Montaner; Mar Hernández-Guillamon; Josune Orbe Journal: Sci Rep Date: 2020-06-25 Impact factor: 4.996
Authors: Carine Poussin; Marco van der Toorn; Sophie Scheuner; Romain Piault; Athanasios Kondylis; Rebecca Savioz; Rémi Dulize; Dariusz Peric; Emmanuel Guedj; Fabio Maranzano; Celine Merg; Moran Morelli; Anne-Laure Egesipe; Stéphanie Johne; Shoaib Majeed; Claudius Pak; Thomas Schneider; Walter K Schlage; Nikolai V Ivanov; Manuel C Peitsch; Julia Hoeng Journal: Arch Toxicol Date: 2021-07-27 Impact factor: 5.153