PMID- 27318830
OWN - NLM
STAT- MEDLINE
DCOM- 20171220
LR  - 20240216
IS  - 1879-1484 (Electronic)
IS  - 0021-9150 (Print)
IS  - 0021-9150 (Linking)
VI  - 251
DP  - 2016 Aug
TI  - A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector 
      induces cardiovascular calcification in mice with no genetic modification.
PG  - 109-118
LID - S0021-9150(16)30256-8 [pii]
LID - 10.1016/j.atherosclerosis.2016.06.011 [doi]
AB  - 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 mug/mL to 20 mug/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.
CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
FAU - Goettsch, Claudia
AU  - Goettsch C
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Hutcheson, Joshua D
AU  - Hutcheson JD
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Hagita, Sumihiko
AU  - Hagita S
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Rogers, Maximillian A
AU  - Rogers MA
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Creager, Michael D
AU  - Creager MD
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Pham, Tan
AU  - Pham T
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Choi, Jung
AU  - Choi J
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Mlynarchik, Andrew K
AU  - Mlynarchik AK
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Pieper, Brett
AU  - Pieper B
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Kjolby, Mads
AU  - Kjolby M
AD  - The Lundbeck Foundation Research Center MIND, Danish Research Institute of 
      Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, 
      Danish Diabetes Academy, Department of Biomedicine, Aarhus University, 8000, 
      Denmark.
FAU - Aikawa, Masanori
AU  - Aikawa M
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; 
      Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Aikawa, Elena
AU  - Aikawa E
AD  - Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; 
      Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic 
      address: eaikawa@partners.org.
LA  - eng
GR  - R01 HL109506/HL/NHLBI NIH HHS/United States
GR  - R01 HL126901/HL/NHLBI NIH HHS/United States
GR  - R01 HL136431/HL/NHLBI NIH HHS/United States
GR  - R01 HL114805/HL/NHLBI NIH HHS/United States
GR  - R01 HL107550/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20160609
PL  - Ireland
TA  - Atherosclerosis
JT  - Atherosclerosis
JID - 0242543
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Receptors, LDL)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 3.4.21.- (Pcsk9 protein, mouse)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - Z020Y8WIJ4 (sortilin)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/metabolism
MH  - Animals
MH  - Atherosclerosis/metabolism
MH  - Calcinosis/*pathology
MH  - Cholesterol/metabolism
MH  - Dependovirus
MH  - Disease Models, Animal
MH  - Female
MH  - Genetic Vectors
MH  - Liver/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microscopy, Fluorescence
MH  - *Mutation
MH  - Proprotein Convertase 9/*genetics
MH  - Proprotein Convertases/genetics
MH  - Receptors, LDL/genetics
PMC - PMC4983246
MID - NIHMS805781
OTO - NOTNLM
OT  - AAV-PCSK9
OT  - Animal model
OT  - Cardiovascular calcification
COIS- Conflict of interest statement SH is an employee of KOWA Company, Ltd., Nagoya, 
      Japan. Other authors have no conflict of interest.
EDAT- 2016/06/20 06:00
MHDA- 2017/12/21 06:00
PMCR- 2017/02/01
CRDT- 2016/06/20 06:00
PHST- 2016/03/07 00:00 [received]
PHST- 2016/04/29 00:00 [revised]
PHST- 2016/06/08 00:00 [accepted]
PHST- 2016/06/20 06:00 [entrez]
PHST- 2016/06/20 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - S0021-9150(16)30256-8 [pii]
AID - 10.1016/j.atherosclerosis.2016.06.011 [doi]
PST - ppublish
SO  - Atherosclerosis. 2016 Aug;251:109-118. doi: 
      10.1016/j.atherosclerosis.2016.06.011. Epub 2016 Jun 9.