AUTHOR=Louloudis Georgios , Ambrosini Samuele , Paneni Francesco , Camici Giovanni G. , Benke Dietmar , Klohs Jan 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.718741

DOI=10.3389/fcvm.2021.718741

ISSN=2297-055X

ABSTRACT=Hypercholesterolemia has previously been induced in the mouse by a single intravenous injection of AAV-based vector harbouring gain-of-function proprotein convertase subtilisin/kexin type 9. Despite the recent emergence of the PCSK9-AAV model, the profile of haematological and coagulation parameters associated with it has yet to be characterized. We injected 1.0 x 1011 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-HDL-cholesterol concentrations, and lower HDL-cholesterol concentrations than control mice. Furthermore, mPCSK9-AAV injected mice on HFD mice 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 was lower in HFD-fed mPCSK9-AAV mice. Therefore, the mPCSK9-AAV is a suitable model of hypercholesterolemia to examine the role thromboinflammtory processes in the pathogenesis of cardiovascular and cerebrovascular diseases.