ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration
The physiological roles of the metalloprotease-proteoglycan ADAMTS7, a drug target in atherosclerosis and vascular restenosis, and its homolog ADAMTS12, are undefined in the cardiovascular system. The objective of the present work was to investigate their roles in mice with genetic inactivation of b...
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Elsevier
2025-03-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976125000078 |
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| author | Timothy J. Mead Sumit Bhutada Niccolò Peruzzi Janet Adegboye Deborah E. Seifert Elisabeth Cahill Jeanne Drinko Eoin Donnellan Anu Guggiliam Zoran Popovic Brian Griffin Karin Tran-Lundmark Suneel S. Apte |
| author_facet | Timothy J. Mead Sumit Bhutada Niccolò Peruzzi Janet Adegboye Deborah E. Seifert Elisabeth Cahill Jeanne Drinko Eoin Donnellan Anu Guggiliam Zoran Popovic Brian Griffin Karin Tran-Lundmark Suneel S. Apte |
| author_sort | Timothy J. Mead |
| collection | DOAJ |
| description | The physiological roles of the metalloprotease-proteoglycan ADAMTS7, a drug target in atherosclerosis and vascular restenosis, and its homolog ADAMTS12, are undefined in the cardiovascular system. The objective of the present work was to investigate their roles in mice with genetic inactivation of both proteases and in relation to the resulting valve defects, to define their proteolytic activities in the matrisome. Here, we demonstrate that Adamts7 and Adamts12 are co-expressed in heart valves and each buffers inactivation of the other by compensatory upregulation. Leaflets of Adamts7−/−;Adamts12−/− aortic valves, but not the respective single mutants, were abnormally shaped at birth, with progressively severe disorganization and enlargement occurring thereafter. Doppler echocardiography showed that Adamts7−/−;Adamts12−/− mice had stenotic and regurgitant aortic valves. We investigated ADAMTS7 and ADAMTS12 substrates relevant to the valve matrisome in secretome libraries from Adamts7−/−;Adamts12−/− cells using the N-terminomics technique Terminal Amine Isotopic Labeling of Substrates (TAILS). Although ADAMTS7 and ADAMTS12 shared several extracellular matrix (ECM) substrates, cleavage sites and sequence preference for each protease were distinct. Adamts7−/−;Adamts12−/− valve leaflets showed accumulation of several of the identified ECM substrates, including periostin, a matricellular protein crucial for cardiac valve homeostasis. We conclude that the myxomatous degeneration in Adamts7−/−;Adamts12−/− valve leaflets reflects a complex disturbance of ECM proteostasis with accumulation of multiple ADAMTS7 and ADAMTS12 ECM substrates, and perturbation of regulatory pathways with roots in ECM, such as TGFβ signaling, which was increased in the mutant valves. |
| format | Article |
| id | doaj-art-4eb25e2ab806425fa1fa047804fb43a6 |
| institution | DOAJ |
| issn | 2772-9761 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-4eb25e2ab806425fa1fa047804fb43a62025-08-20T03:01:42ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612025-03-011110028810.1016/j.jmccpl.2025.100288ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degenerationTimothy J. Mead0Sumit Bhutada1Niccolò Peruzzi2Janet Adegboye3Deborah E. Seifert4Elisabeth Cahill5Jeanne Drinko6Eoin Donnellan7Anu Guggiliam8Zoran Popovic9Brian Griffin10Karin Tran-Lundmark11Suneel S. Apte12Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH, USA; Correspondence to: T. Mead, Department of Pediatrics, Case Western Reserve University School of Medicine, 2103 Cornell Road WRB4529, Cleveland, OH 44106, USA.Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Experimental Medical Science and Wallenberg Center for Molecular Medicine, Lund University, Lund, SwedenDepartment of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USADepartment of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USADepartment of Experimental Medical Science and Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; The Pediatric Heart Center, Skane University Hospital, Lund, SwedenDepartment of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA; Correspondence to: S.S. Apte, Department of Biomedical Engineering-ND20, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.The physiological roles of the metalloprotease-proteoglycan ADAMTS7, a drug target in atherosclerosis and vascular restenosis, and its homolog ADAMTS12, are undefined in the cardiovascular system. The objective of the present work was to investigate their roles in mice with genetic inactivation of both proteases and in relation to the resulting valve defects, to define their proteolytic activities in the matrisome. Here, we demonstrate that Adamts7 and Adamts12 are co-expressed in heart valves and each buffers inactivation of the other by compensatory upregulation. Leaflets of Adamts7−/−;Adamts12−/− aortic valves, but not the respective single mutants, were abnormally shaped at birth, with progressively severe disorganization and enlargement occurring thereafter. Doppler echocardiography showed that Adamts7−/−;Adamts12−/− mice had stenotic and regurgitant aortic valves. We investigated ADAMTS7 and ADAMTS12 substrates relevant to the valve matrisome in secretome libraries from Adamts7−/−;Adamts12−/− cells using the N-terminomics technique Terminal Amine Isotopic Labeling of Substrates (TAILS). Although ADAMTS7 and ADAMTS12 shared several extracellular matrix (ECM) substrates, cleavage sites and sequence preference for each protease were distinct. Adamts7−/−;Adamts12−/− valve leaflets showed accumulation of several of the identified ECM substrates, including periostin, a matricellular protein crucial for cardiac valve homeostasis. We conclude that the myxomatous degeneration in Adamts7−/−;Adamts12−/− valve leaflets reflects a complex disturbance of ECM proteostasis with accumulation of multiple ADAMTS7 and ADAMTS12 ECM substrates, and perturbation of regulatory pathways with roots in ECM, such as TGFβ signaling, which was increased in the mutant valves.http://www.sciencedirect.com/science/article/pii/S2772976125000078ADAMTSExtracellular matrixMetalloproteinaseProteoglycanMyxomatous valveHeart valve |
| spellingShingle | Timothy J. Mead Sumit Bhutada Niccolò Peruzzi Janet Adegboye Deborah E. Seifert Elisabeth Cahill Jeanne Drinko Eoin Donnellan Anu Guggiliam Zoran Popovic Brian Griffin Karin Tran-Lundmark Suneel S. Apte ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration Journal of Molecular and Cellular Cardiology Plus ADAMTS Extracellular matrix Metalloproteinase Proteoglycan Myxomatous valve Heart valve |
| title | ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration |
| title_full | ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration |
| title_fullStr | ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration |
| title_full_unstemmed | ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration |
| title_short | ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration |
| title_sort | adamts7 a target in atherosclerosis cooperates with its homolog adamts12 to protect against myxomatous valve degeneration |
| topic | ADAMTS Extracellular matrix Metalloproteinase Proteoglycan Myxomatous valve Heart valve |
| url | http://www.sciencedirect.com/science/article/pii/S2772976125000078 |
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