ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1
BACKGROUND: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis.
METHODS: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques.
RESULTS: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site.
CONCLUSIONS: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
Circulation research - 133(2023), 8 vom: 29. Sept., Seite 674-686 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sharifi, M Amin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.10.2023 Date Revised 05.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1161/CIRCRESAHA.123.322737 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361732031 |
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| 245 | 1 | 0 | |a ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis | ||
| 520 | |a METHODS: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques | ||
| 520 | |a RESULTS: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site | ||
| 520 | |a CONCLUSIONS: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events | ||
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| 700 | 1 | |a Wierer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Tan An |e verfasserin |4 aut | |
| 700 | 1 | |a Milic, Jelena |e verfasserin |4 aut | |
| 700 | 1 | |a Moggio, Aldo |e verfasserin |4 aut | |
| 700 | 1 | |a Sachs, Nadja |e verfasserin |4 aut | |
| 700 | 1 | |a von Scheidt, Moritz |e verfasserin |4 aut | |
| 700 | 1 | |a Hinterdobler, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Werner, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Stiller, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Aherrahrou, Zouhair |e verfasserin |4 aut | |
| 700 | 1 | |a Erdmann, Jeanette |e verfasserin |4 aut | |
| 700 | 1 | |a Zaliani, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Graettinger, Mira |e verfasserin |4 aut | |
| 700 | 1 | |a Reinshagen, Jeanette |e verfasserin |4 aut | |
| 700 | 1 | |a Gul, Sheraz |e verfasserin |4 aut | |
| 700 | 1 | |a Gribbon, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Maegdefessel, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Bernhagen, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Sager, Hendrik B |e verfasserin |4 aut | |
| 700 | 1 | |a Mann, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Schunkert, Heribert |e verfasserin |4 aut | |
| 700 | 1 | |a Kessler, Thorsten |e verfasserin |4 aut | |
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