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ADAMTS 13 modulates atherosclerotic plaque progression in mice via a VWF ‐dependent mechanism
Author(s) -
Gandhi C.,
Ahmad A.,
Wilson K. M.,
Chauhan A. K.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12456
Subject(s) - adamts13 , apolipoprotein e , von willebrand factor , medicine , aortic sinus , endocrinology , knockout mouse , chemistry , apolipoprotein b , cholesterol , aorta , platelet , receptor , disease
Summary Background ADAMTS 13 reduces the adhesiveness of hyperactive ultra‐large von Willebrand factor ( ULVWF ) multimers by cleaving them into smaller, less active multimers. Recently, we and others have demonstrated that ADAMTS 13 reduces atherosclerosis in hypercholesteremic apolipoprotein E ( ApoE −/−) deficient mice. It is not known whether ADAMTS 13 modulates atherosclerosis directly or indirectly by cleaving ULVWF multimers. Objective We generated triple knockout Adamts 13−/−/ Vwf −/−/ ApoE −/− mice to determine whether ADAMTS 13 modulates atherosclerosis through its proteolytic effects on VWF or other potential mechanisms. Methods Female mice were fed a high‐fat Western diet beginning at 6 weeks of age until they were sacrificed at 4 months. We compared the extent of atherosclerosis in the serial cross‐sections of the aortic sinus using the Verhoeff‐Van Gieson stain. Macrophage and neutrophil infiltration were quantified by immunohistochemistry. Under plain polarized light interstitial collagen content in the serial cross‐sections of the aortic sinus was quantified using picrosirius red stain. Results Deficiency of VWF in Adamts 13−/−/ ApoE −/− mice ( Adamts13 −/−/ Vwf −/−/ ApoE −/−) completely reversed exacerbated atherosclerosis ( P < 0.05 vs. Adamts 13−/−/ ApoE −/− mice). The lesion size, macrophage and neutrophil infiltration in the aortic sinus of Adamts 13−/−/ Vwf −/−/ ApoE −/− mice were significantly decreased compared with Adamts 13−/−/ ApoE −/− mice ( P < 0.05), but similar to Vwf −/−/ ApoE −/− mice. Additionally, interstitial collagen content in the aortic sinus of Adamts13 − / − /Vwf − / − /ApoE −/− mice was significantly reduced compared with Adamts13 −/−/ ApoE −/− mice ( P < 0.05), but similar to Vwf − / − /ApoE −/− mice. Total cholesterol and triglyceride levels were similar among groups. Conclusions ADAMTS 13 modulates inflammatory plaque progression in hypercholesterolemic mice through a VWF ‐dependent mechanism. These findings provide further evidence on the pathophysiological role for the ADAMTS 13/ VWF axis in atherosclerosis.