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ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice
Chintan Gandhi1, Mohammad Moshahid Khan, Steven R Lentz
1Department of Internal Medicine, University of Iowa, Iowa City, USA.
Abstract:
ADAMTS13, a metalloprotease, plays a pivotal role in preventing spontaneous microvascular thrombosis by cleaving hyperactive ultra large von Willebrand factor multimers into smaller, less active multimers. Reduced ADAMTS13 activity in plasma has been described in many diseases associated with systemic inflammation. It remains uncertain, however, whether ADAMTS13 contributes to disease pathogenesis or rather simply serves as an inflammation-associated marker. We hypothesized that, by decreasing vascular inflammation, ADAMTS13 reduces the development of early atherosclerotic plaques. Using intravital fluorescence microscopy, we observed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation at the carotid sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice fed a high-fat Western diet. At 4 months of age, there was a significant increase in atherosclerosis in the aorta and aortic sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice. Interestingly, we detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice, suggesting that the atherosclerotic lesions in these mice were not only larger but also more inflammatory. These findings reveal a new functional role for the antithrombotic enzyme ADAMTS13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis.
Insights
The metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) reduces vascular inflammation and atherosclerosis. Studies show Adamts13(-/-)/ApoE(-/-) mice exhibit increased plaque formation and macrophage recruitment.
Area of Science:
- Vascular Biology
- Immunology
- Biochemistry
Background:
- ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves von Willebrand factor multimers, preventing thrombosis.
- Reduced ADAMTS13 activity is linked to inflammatory diseases, but its role in pathogenesis is unclear.
Purpose of the Study:
- To investigate the role of ADAMTS13 in vascular inflammation and early atherosclerosis.
- To test the hypothesis that ADAMTS13 reduces atherosclerotic plaque development by decreasing vascular inflammation.
Main Methods:
- Intravital fluorescence microscopy was used to assess leukocyte adhesion and plaque formation in Adamts13(-/-)/ApoE(-/-) mice and ApoE(-/-) mice on a high-fat diet.
- Atherosclerosis was quantified in the aorta and aortic sinus at 4 months of age.
- Macrophage recruitment to atherosclerotic plaques was analyzed.
Main Results:
- Adamts13(-/-)/ApoE(-/-) mice showed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation compared to ApoE(-/-) mice.
- Significant increases in atherosclerosis were observed in the aorta and aortic sinus of Adamts13(-/-)/ApoE(-/-) mice.
- A 2-fold increase in macrophage recruitment to plaques in Adamts13(-/-)/ApoE(-/-) mice indicated more inflammatory lesions.
Conclusions:
- ADAMTS13 plays a protective role in early atherosclerosis by reducing vascular inflammation.
- The findings reveal a novel function for ADAMTS13 in mitigating excessive inflammation and plaque formation in atherosclerosis.
