ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism

被引：37
作者：
Gandhi, C. [1 ]
Ahmad, A. [1 ]
Wilson, K. M. [1 ]
Chauhan, A. K. [1 ]
机构：
[1] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
来源：
JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2014年 / 12卷 / 02期
关键词：
ADAMTS13; protein; atherosclerosis; inflammation; neutrophils; thrombosis; von Willebrand Factor; VON-WILLEBRAND-FACTOR; MYOCARDIAL ISCHEMIA/REPERFUSION INJURY; ISCHEMIC-STROKE; MOUSE MODEL; INFLAMMATION; DEFICIENCY; THROMBOSIS; ADHESION;
D O I：
10.1111/jth.12456
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
BackgroundADAMTS13 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. ObjectiveWe generated triple knockout Adamts13-/-/Vwf-/-/ApoE-/- mice to determine whether ADAMTS13 modulates atherosclerosis through its proteolytic effects on VWF or other potential mechanisms. MethodsFemale mice were fed a high-fat Western diet beginning at 6weeks of age until they were sacrificed at 4months. 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. ResultsDeficiency 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. ConclusionsADAMTS13 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.
引用
收藏
页码：255 / 260
页数：6
相关论文
共 24 条
[1]   Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura [J].
Banno, F ;
Kokame, K ;
Okuda, T ;
Honda, S ;
Miyata, S ;
Kato, H ;
Tomiyama, Y ;
Miyata, T .
BLOOD, 2006, 107 (08) :3161-3166
[2]   Systemic antithrombotic effects of ADAMTS13 [J].
Chauhan, AK ;
Motto, DG ;
Lamb, CB ;
Bergmeier, W ;
Dockal, M ;
Plaimauer, B ;
Scheiflinger, F ;
Ginsburg, D ;
Wagner, DD .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (03) :767-776
[3]   ADAMTS13: a new link between thrombosis and inflammation [J].
Chauhan, Anil K. ;
Kisucka, Janka ;
Brill, Alexander ;
Walsh, Meghan T. ;
Scheiflinger, Friedrich ;
Wagner, Denisa D. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2008, 205 (09) :2065-2074
[4]   The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis [J].
Chauhan, Anil K. ;
Walsh, Meghan T. ;
Zhu, Guojing ;
Ginsburg, David ;
Wagner, Denisa D. ;
Motto, David G. .
BLOOD, 2008, 111 (07) :3452-3457
[5]   Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice [J].
De Meyer, Simon F. ;
Savchenko, Alexander S. ;
Haas, Michael S. ;
Schatzberg, Daphne ;
Carroll, Michael C. ;
Schiviz, Alexandra ;
Dietrich, Barbara ;
Rottensteiner, Hanspeter ;
Scheiflinger, Friedrich ;
Wagner, Denisa D. .
BLOOD, 2012, 120 (26) :5217-5223
[6]   Binding of von Willebrand Factor to Collagen and Glycoprotein Ibα, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice-Brief Report [J].
De Meyer, Simon F. ;
Schwarz, Tobias ;
Deckmyn, Hans ;
Denis, Cecile V. ;
Nieswandt, Bernhard ;
Stoll, Guido ;
Vanhoorelbeke, Karen ;
Kleinschnitz, Christoph .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2010, 30 (10) :1949-1951
[7]   A mouse model of severe von Willebrand disease:: Defects in hemostasis and thrombosis [J].
Denis, C ;
Methia, N ;
Frenette, PS ;
Rayburn, H ;
Ullman-Culleré, M ;
Hynes, RO ;
Wagner, DD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (16) :9524-9529
[8]   ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction [J].
Doi, Masaaki ;
Matsui, Hideto ;
Takeda, Yukiji ;
Saito, Yoshihiko ;
Takeda, Maiko ;
Matsunari, Yasunori ;
Nishio, Kenji ;
Shima, Midori ;
Banno, Fumiaki ;
Akiyama, Masashi ;
Kokame, Koichi ;
Miyata, Toshiyuki ;
Sugimoto, Mitsuhiko .
THROMBOSIS AND HAEMOSTASIS, 2012, 108 (06) :1236-1238
[9]   ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion [J].
Fujioka, Masayuki ;
Hayakawa, Kazuhide ;
Mishima, Kenichi ;
Kunizawa, Ai ;
Irie, Keiichi ;
Higuchi, Sei ;
Nakano, Takafumi ;
Muroi, Carl ;
Fukushima, Hidetada ;
Sugimoto, Mitsuhiko ;
Banno, Fumiaki ;
Kokame, Koichi ;
Miyata, Toshiyuki ;
Fujiwara, Michihiro ;
Okuchi, Kazuo ;
Nishio, Kenji .
BLOOD, 2010, 115 (08) :1650-1653
[10]   ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice [J].
Gandhi, Chintan ;
Motto, David G. ;
Jensen, Melissa ;
Lentz, Steven R. ;
Chauhan, Anil K. .
BLOOD, 2012, 120 (26) :5224-5230
123