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Adeno-Associated Virus-Mediated Gain-of-Function mPCSK9 Expression in the Mouse Induces Hypercholesterolemia, Monocytosis, Neutrophilia, and a Hypercoagulative State

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Louloudis Georgios, Ambrosini Samuele, Paneni Francesco, Camici Giovanni G., Benke Dietmar, Klohs Jan,
Project Investigating the effects of hypercholesterolemia on neutrophil-mediated thromboinflammation after cerebral ischemia
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Original article (peer-reviewed)

Journal Frontiers in Cardiovascular Medicine
Volume (Issue) 8
Page(s) 1
Title of proceedings Frontiers in Cardiovascular Medicine
DOI 10.3389/fcvm.2021.718741

Open Access

URL http://doi.org/10.3389/fcvm.2021.718741
Type of Open Access Publisher (Gold Open Access)

Abstract

Hypercholesterolemia has previously been induced in the mouse by a single intravenous injection of adeno-associated virus (AAV)-based vector harboring gain-of-function pro-protein convertase subtilisin/kexin type 9. Despite the recent emergence of the PCSK9-AAV model, the profile of hematological and coagulation parameters associated with it has yet to be characterized. We injected 1.0 × 10 11 viral particles of mPCSK9-AAV or control AAV into juvenile male C57BL/6N mice and fed them with either a Western-type high-fat diet (HFD) or standard diet over the course of 3 weeks. mPCSK9-AAV mice on HFD exhibited greater plasma PCSK9 concentration and lower low-density lipoprotein levels, concomitant with increased total cholesterol and non-high-density lipoprotein (non-HDL)-cholesterol concentrations, and lower HDL-cholesterol concentrations than control mice. Furthermore, mPCSK9-AAV-injected mice on HFD exhibited no signs of atherosclerosis at 3 weeks after the AAV injection. Hypercholesterolemia was associated with a thromboinflammatory phenotype, as neutrophil levels, monocyte levels, and neutrophil-to-lymphocyte ratios were higher and activated partial thromboplastin times (aPTTs) was lower in HFD-fed mPCSK9-AAV mice. Therefore, the mPCSK9-AAV is a suitable model of hypercholesterolemia to examine the role of thromboinflammatory processes in the pathogenesis of cardiovascular and cerebrovascular diseases.
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