ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Chintan Gandhi; Mohammad Moshahid Khan; Steven R Lentz; Anil K Chauhan

doi:10.1182/blood-2011-09-376202

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ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Journal article

Open access

Peer reviewed

ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Chintan Gandhi, Mohammad Moshahid Khan, Steven R Lentz and Anil K Chauhan

Blood, Vol.119(10), pp.2385-2391

03/08/2012

DOI: 10.1182/blood-2011-09-376202

PMCID: PMC3311260

PMID: 22123843

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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.

Immunohistochemistry

Metalloendopeptidases - genetics

Leukocytes - pathology

Vasculitis - metabolism

Plaque, Atherosclerotic - genetics

Male

Metalloendopeptidases - metabolism

Aorta - metabolism

Apolipoproteins E - metabolism

Collagen Type II - metabolism

Sinus of Valsalva - metabolism

Vasculitis - genetics

Time Factors

Lipids - blood

Dietary Fats - administration & dosage

Female

Sinus of Valsalva - pathology

Vasculitis - blood

Collagen Type I - metabolism

Plaque, Atherosclerotic - metabolism

Mice, Inbred C57BL

ADAMTS13 Protein

Cell Adhesion

Mice, Knockout

Plaque, Atherosclerotic - etiology

Aorta - pathology

Macrophages - metabolism

Animals

Apolipoproteins E - genetics

Mice

Dietary Fats - toxicity

Leukocytes - metabolism

Microscopy, Fluorescence

Details

Title: Subtitle: ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice
Creators: Chintan Gandhi - Department of Internal Medicine, University of Iowa, Iowa City, USA
Mohammad Moshahid Khan
Steven R Lentz
Anil K Chauhan
Resource Type: Journal article
Publication Details: Blood, Vol.119(10), pp.2385-2391
DOI: 10.1182/blood-2011-09-376202
PMID: 22123843
PMCID: PMC3311260
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: HL063943 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS NS024621 / NINDS NIH HHS R01 HL063943 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS
Language: English
Date published: 03/08/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094353002771

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