BACKGROUND: ADAMTS13 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 ADAMTS13 reduces atherosclerosis in hypercholesteremic apolipoprotein E (ApoE-/-) deficient mice. It is not known whether ADAMTS13 modulates atherosclerosis directly or indirectly by cleaving ULVWF multimers. OBJECTIVE: We generated triple knockout Adamts13-/-/Vwf-/-/ApoE-/- mice to determine whether ADAMTS13 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 Adamts13-/-/ApoE-/- mice (Adamts13-/-/Vwf-/-/ApoE-/-) completely reversed exacerbated atherosclerosis (P < 0.05 vs. Adamts13-/-/ApoE-/- mice). The lesion size, macrophage and neutrophil infiltration in the aortic sinus of Adamts13-/-/Vwf-/-/ApoE-/- mice were significantly decreased compared with Adamts13-/-/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: ADAMTS13 modulates inflammatory plaque progression in hypercholesterolemic mice through a VWF-dependent mechanism. These findings provide further evidence on the pathophysiological role for the ADAMTS13/VWF axis in atherosclerosis.
BACKGROUND:ADAMTS13 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 ADAMTS13 reduces atherosclerosis in hypercholesteremicapolipoprotein E (ApoE-/-) deficient mice. It is not known whether ADAMTS13 modulates atherosclerosis directly or indirectly by cleaving ULVWF multimers. OBJECTIVE: We generated triple knockout Adamts13-/-/Vwf-/-/ApoE-/- mice to determine whether ADAMTS13 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 Adamts13-/-/ApoE-/- mice (Adamts13-/-/Vwf-/-/ApoE-/-) completely reversed exacerbated atherosclerosis (P < 0.05 vs. Adamts13-/-/ApoE-/- mice). The lesion size, macrophage and neutrophil infiltration in the aortic sinus of Adamts13-/-/Vwf-/-/ApoE-/- mice were significantly decreased compared with Adamts13-/-/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:ADAMTS13 modulates inflammatory plaque progression in hypercholesterolemicmice through a VWF-dependent mechanism. These findings provide further evidence on the pathophysiological role for the ADAMTS13/VWF axis in atherosclerosis.
Authors: Miruna Popa; Sibgha Tahir; Julia Elrod; Su Hwan Kim; Florian Leuschner; Thorsten Kessler; Peter Bugert; Ulrich Pohl; Andreas H Wagner; Markus Hecker Journal: Proc Natl Acad Sci U S A Date: 2018-05-23 Impact factor: 11.205
Authors: Harshvardhan Upreti; Jamil Kasmani; Kathryn Dane; Evan M Braunstein; Michael B Streiff; Satish Shanbhag; Alison R Moliterno; C John Sperati; Rebecca F Gottesman; Robert A Brodsky; Thomas S Kickler; Shruti Chaturvedi Journal: Blood Date: 2019-08-20 Impact factor: 22.113
Authors: Weihui Shentu; Koya Ozawa; The Anh Nguyen; Melinda D Wu; William Packwood; Aris Xie; Matthew A Muller; Eran Brown; Matthew W Hagen; José A López; Jonathan R Lindner Journal: J Am Soc Echocardiogr Date: 2020-11-27 Impact factor: 5.251