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Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Conditional knockout of membrane-type I matrix metalloproteinase in smooth muscle cells of adult mice alleviates
Suha Jarad1, Hong-Mei Gu2, Daniel Huang1
1Department of Biochemistry, Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Canada.
Insights
Inhibiting membrane-type I matrix metalloproteinase (MMP14) in adult mice reduced atherosclerosis development and promoted plaque regression. This suggests MMP14 is a potential therapeutic target for atherosclerotic cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Atherosclerotic cardiovascular disease (ASCVD) remains a leading global health concern, with significant residual risk despite current treatments.
- Vascular smooth muscle cell (SMC) dedifferentiation is a key driver of atherosclerosis progression.
- Membrane-type I matrix metalloproteinase (MT1-MMP/MMP14) facilitates SMC dedifferentiation, but its role in established adult atherosclerosis is unclear.
Purpose of the Study:
- To investigate the role of SMC-specific MMP14 in adult mice with existing atherosclerotic plaques.
- To determine the therapeutic potential of inhibiting MMP14 in the context of atherosclerosis.
Main Methods:
- Developed an inducible, SMC-specific MMP14 knockout mouse model.
- Assessed cardiac and vascular function via echocardiography and wire myography.
- Evaluated atherosclerosis progression/regression in Ldlr-/- mice lacking SMC MMP14, using snRNA-seq for SMC population analysis.
Main Results:
- SMC MMP14 deficiency reduced atherosclerosis development and enhanced plaque regression in Ldlr-/- mice.
- snRNA-seq showed increased fibroblast-like SMCs and decreased foam cell-like SMCs in MMP14-deficient mice.
- Inhibition of SMC MMP14 decreased SMC proliferation and migration, with reduced PDGFR-β signaling.
Conclusions:
- SMC MMP14 actively promotes atherosclerosis in adult mice.
- Targeting MMP14 may be a viable strategy to reduce atherosclerotic plaque burden and progression.
- MMP14 inhibition impacts SMC phenotype, migration, and PDGF signaling pathways.
Background:
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. Despite effective lipid-lowering treatments, substantial residual risks remain. In atherosclerosis, vascular smooth muscle cells (SMCs) undergo dedifferentiation, promoting disease progression. Membrane-type I matrix metalloproteinase (MT1-MMP/MMP14) promotes SMC dedifferentiation. However, the effect of inhibiting MMP14 in adults, particularly those with existing atherosclerotic plaques, is unclear.
Methods:
We developed an inducible conditional SMC-specific MMP14 knockout mouse model. Cardiac and vascular function were assessed using echocardiography and wire myography, respectively. Atherosclerosis progression and regression were evaluated in Ldlr-/- mice with or without MMP14 deficiency. snRNA-seq of the aortas from Ldlr-/- mice was performed to determine the effect on SMC populations.
Results:
MMP14 expression was elevated in SMCs within fibroatheroma compared with the pathological intima thickening in coronary aortas from patients with ASCVD. Conditional knockout of SMC MMP14 in adult mice did not change plasma cholesterol levels or basic cardiac and vascular function. However, atherosclerosis development was reduced, and the regression of existing plaques was enhanced in Ldlr-/- mice lacking SMC MMP14. snRNA-seq revealed increased fibroblast-like SMCs and reduced foam cell-like SMCs in MMP14-deficient Ldlr-/- mice compared to Ldlr-/- mice. Furthermore, SMC MMP14 deficiency decreased SMC proliferation and migration, accompanied by reduced platelet-derived growth factor receptor (PDGFR) β levels and attenuated PDGF signalling.
Conclusion:
SMC MMP14 promotes atherosclerosis in adult mice, likely through reducing PDGF signalling and inhibiting SMC migration and proliferation.
