Genetic ablation of Adamts13 gene dramatically accelerates the formation of early atherosclerosis in a murine model.
OBJECTIVE
ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves von Willebrand factor, thereby modulating thrombosis and inflammation. Low plasma ADAMTS13 activity is associated with cardiovascular events, including myocardial and cerebral infarction. Here, we investigated the role of ADAMTS13 in the development of early atherosclerosis in a murine model.


RESULTS
Apolipoprotein E-null (ApoE(-/-)) and Adamts13-null (Adamts13(-/-)) ApoE(-/-) mice were fed with a high-fat Western diet for 12 weeks. Atherosclerotic lesions in the aorta and aortic roots were quantified after staining. Leukocyte rolling and adhesion onto cremaster venules after oxidative injury were determined by intravital microscopy. Although plasma cholesterol levels were largely similar in both groups, the extent of atherosclerotic lesions in the aorta en face and in the aortic roots in the Adamts13(-/-)ApoE(-/-) mice increased ≈ 5.5-fold (P=0.0017) and ≈ 6.1-fold (P=0.0037), respectively. In addition, the ratio of plasma high- to low-molecular-weight von Willebrand factor multimers increased ≈ 3-fold. The leukocyte rolling velocities were significantly reduced (P<0.001), with an increased number of leukocyte rolling (P=0.0026) and macrophage infiltration into the atherosclerotic lesions in the Adamts13(-/-)ApoE(-/-) mice.


CONCLUSIONS
Our results suggest that ADAMTS13 plays a critical role in modulating the development of early atherosclerosis, likely through the proteolytic cleavage of ultra-large von Willebrand factor multimers, thereby inhibiting platelet deposition and inflammation.
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, 816G ARC, Philadelphia, PA 19104, USA.
Sheng-Yu
SY
Jin
Junichiro
J
Tohyama
Robert C
RC
Bauer
Na Nora
NN
Cao
Daniel J
DJ
Rader
X Long
XL
Zheng
D000071120:ADAMTS13 Protein; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology*; D002448:Cell Adhesion; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D007962:Leukocytes / Q000502:physiology; D008666:Metalloendopeptidases / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014841:von Willebrand Factor / Q000502:physiology
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein