Key result
In atherosclerotic mouse models, deficiency of Adamts-7 significantly increased plaque collagen content compared to controls (33.95% vs 16.8%, p=0.004) by reducing TIMP-1 degradation and MMP-9 activity.
Why the study?
Although the ADAMTS7 locus is associated with CAD and its deficiency reduces plaque formation, the molecular mechanisms and downstream targets mediating atherosclerosis risk remained unidentified.
Does ADAMTS-7 deficiency prevent TIMP-1 degradation and increase collagen content in atherosclerotic plaques in Apoe-/- mice?
Does ADAMTS-7 deficiency prevent TIMP-1 degradation and increase collagen content in atherosclerotic plaques in Apoe-/- mice?
ADAMTS-7 promotes atherosclerotic plaque instability by degrading TIMP-1 and increasing MMP-9 activity, suggesting ADAMTS-7 inhibition as a potential therapeutic strategy.
Suggests Adamts-7 as a plaque-stability target; leaves open translation to human outcomes.
Background The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease (CAD). Lack of the extracellular matrix (ECM) protease ADAMTS-7 was shown to reduce atherosclerotic plaque formation. Objective To identify molecular mechanisms and downstream targets of ADAMTS-7 mediating 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, co-immunoprecipitation, and Förster resonance energy transfer (FRET)-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 tissue inhibitor of metalloproteases 1 (Timp-1). In co-immunoprecipitation 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 matrix metalloprotease 9 (MMP-9) As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after 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. In order to facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim to decrease TIMP-1 degradation, we designed a FRET-based assay targeting the ADAMTS-7 catalytic site. Conclusion 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 genome-wide significantly associated with CAD. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for reduction of atherosclerosis-related events.
No takes yet. Share an insight, caveat, or question.
Sharifi et al. (2023) studied Atherosclerosis (n=20). Adamts-7 knockout vs. Wild-type Adamts-7 (Apoe-/- mice) was evaluated on Plaque collagen content (p=0.004). In atherosclerotic mouse models, deficiency of Adamts-7 significantly increased plaque collagen content compared to controls (33.95% vs 16.8%, p=0.004) by reducing TIMP-1 degradation and MMP-9 activity.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: