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Lysosomal cysteine proteases in atherosclerosis
Jian Liu1, Galina K Sukhova, Jiu-Song Sun
1Department of Molecular and Cell Biology, School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
This study explores how lysosomal cysteine proteases contribute to atherosclerosis. These enzymes, including cathepsins S, K, and L, break down elastin and collagen in arterial walls. Human atherosclerotic tissues show higher activity of these proteases compared to healthy tissues. The study finds that reduced levels of cystatin C, a natural inhibitor, may tip the balance in favor of matrix remodeling. Inhibiting protease activity with E64d reduces elastin degradation. Inflammatory cytokines increase protease expression in cultured cells. Mice lacking cathepsin S show fewer signs of arterial remodeling, suggesting these proteases play a key role in atherogenesis.
Area of Science:
- Cardiovascular disease mechanisms in pathology
- Matrix remodeling in vascular biology
- Inflammatory enzyme regulation in atherosclerosis
Background:
Atherosclerosis involves structural changes in arterial walls. While matrix metalloproteinases and serine proteases are known contributors, recent evidence suggests lysosomal cysteine proteases also play a role. Human and animal studies indicate these proteases may contribute to disease progression. Healthy tissues typically maintain a balance between proteases and their inhibitors. In atherosclerosis, this balance appears disrupted. Elastin and collagen degradation are key features of the disease. Cystatin C levels are lower in diseased tissue, suggesting reduced inhibition. This imbalance may drive vascular remodeling.
Purpose Of The Study:
This study aimed to investigate the role of lysosomal cysteine proteases in atherosclerosis. Researchers sought to determine if these proteases contribute to arterial remodeling. They focused on cathepsins S, K, and L, which degrade elastin and collagen. The study also examined the impact of cystatin C levels on protease activity. By comparing healthy and atherosclerotic tissues, the team explored protease expression patterns. They tested the effect of E64d, a cysteine protease inhibitor, on elastolysis. Inflammatory cytokines were also studied for their influence on protease activity. The goal was to clarify how these proteases affect atherogenesis.
Main Methods:
The study used human atheromatous tissue extracts and compared them to healthy donor samples. Elastolytic activity was measured in vitro using these extracts. Researchers tested the effect of E64d on protease activity. Cultured macrophages, smooth muscle cells, and endothelial cells were exposed to inflammatory cytokines. Expression and secretion of active cathepsins were analyzed. Cathepsin S-deficient cells were used to assess protease function. LDL receptor-null mice lacking cathepsin S were studied in vivo. The impact of protease inhibition on arterial remodeling was evaluated.
Main Results:
Human atherosclerotic tissues showed higher elastolytic activity than healthy tissues. Cathepsins S, K, and L were overexpressed in atherosclerotic lesions. Cystatin C levels were reduced in these tissues, suggesting less inhibition. E64d significantly reduced elastolysis in vitro. Inflammatory cytokines increased protease expression in cultured cells. These proteases degraded extracellular elastin and collagen. Cathepsin S-deficient cells showed impaired elastolytic activity. Mice lacking cathepsin S had reduced leukocyte infiltration and neovascularization.
Conclusions:
The findings suggest lysosomal cysteine proteases contribute to atherogenesis. Cathepsins S, K, and L appear to drive vascular remodeling. Reduced cystatin C levels may tip the protease-inhibitor balance. E64d inhibits elastolysis, confirming protease involvement. Inflammatory cytokines enhance protease activity in multiple cell types. Cathepsin S deficiency reduces arterial remodeling in mice. These results support a role for cysteine proteases in atherosclerosis. Further work is needed to clarify clinical implications.
Frequently Asked Questions
These proteases, including cathepsins S, K, and L, degrade elastin and collagen in atherosclerotic lesions. Their activity is increased in diseased tissue, suggesting a role in vascular remodeling.
E64d, a cysteine protease inhibitor, reduces elastolytic activity in human atheromatous tissue extracts, indicating protease involvement in elastin degradation.
Cystatin C inhibits cysteine proteases. Lower levels in atherosclerotic tissue suggest reduced inhibition, which may promote extracellular matrix degradation.
Inflammatory cytokines increase expression and secretion of active cathepsins in macrophages, smooth muscle cells, and endothelial cells, enhancing elastin and collagen degradation.
Cathepsin S-deficient cells show significantly impaired elastolytic and collagenolytic activity, suggesting this protease is crucial for matrix remodeling in atherogenesis.
Mice lacking cathepsin S show reduced leukocyte infiltration, elastic lamina degradation, and neovascularization, indicating the enzyme's role in arterial remodeling.