A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification

被引：100

作者：

Goettsch, Claudia ^{[1
]}

Hutcheson, Joshua D. ^{[1
]}

Hagita, Sumihiko ^{[1
]}

Rogers, Maximillian A. ^{[1
]}

Creager, Michael D. ^{[1
]}

Tan Pham ^{[1
]}

Choi, Jung ^{[1
]}

Mlynarchik, Andrew K. ^{[1
]}

Pieper, Brett ^{[1
]}

Kjolby, Mads ^{[3
]}

Aikawa, Masanori ^{[1
,2
]}

Aikawa, Elena ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Ctr Interdisciplinary Cardiovasc Sci, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Ctr Excellence Vasc Biol, Boston, MA 02115 USA

[3] Aarhus Univ, Dept Biomed, Danish Diabet Acad,Lundbeck Fdn Res Ctr MIND, Nord EMBL Partnership Mol Med,Danish Res Inst Tra, DK-8000 Aarhus, Denmark

来源：

ATHEROSCLEROSIS | 2016年 / 251卷

基金：

美国国家卫生研究院;

关键词：

Cardiovascular calcification; AAV-PCSK9; Animal model; ATHEROSCLEROSIS; HYPOTHESIS; INDUCTION; RUPTURE;

D O I：

10.1016/j.atherosclerosis.2016.06.011

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background and aims: Studying atherosclerotic calcification in vivo requires mouse models with genetic modifications. Previous studies showed that injection of recombinant adeno-associated virus vector (AAV) encoding a gain-of-function mutant PCSK9 into mice promotes atherosclerosis. We aimed to study cardiovascular calcification induced by PCSK9 AAV in C57BL/6J mice. Methods: 10 week-old C57BL/6J mice received a single injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9). Ldlr(-/-) mice served as positive controls. Mice consumed a high-fat, high-cholesterol diet for 15 or 20 weeks. Aortic calcification was assessed by fluorescence reflectance imaging (FRI) of a near-infrared calcium tracer. Results: Serum levels of PCSK9 (0.14 mu g/mL to 20 mu g/mL, p < 0.01) and total cholesterol (82 mg/dL to 820 mg/dL, p < 0.01) increased within one week after injection and remained elevated for 20 weeks. Atherosclerotic lesion size was similar between PCSK9 AAV and Ldlr(-/-) mice. Aortic calcification was 0.01% +/- 0.01 in PCSK9 AAV mice and 15.3% +/- 6.1 in Ldlr(-/-) mice at 15 weeks (p < 0.01); by 20 weeks, the PCSK9 AAV mice aortic calcification grew to 12.4% +/- 4.9. Tissue non-specific alkaline phosphatase activity was similar in PCSK9 AAV mice and Ldlr(-/-) mice at 15 and 20 weeks, respectively. As example of the utility of this model in testing modulators of calcification in vivo, PCSK9 AAV injection to sortilin-deficient mice demonstrated reduced aortic calcification by 46.3% (p < 0.05) compared to littermate controls. Conclusions: A single injection of gain-of-function PCSK9 AAV into C57BL/6J mice is a useful tool to study cardiovascular calcification in mice with no genetic manipulation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

引用

页码：109 / 118

页数：10

共 17 条

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