The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction

William Coles Keeter; Nigeste M Carter; Jerry L Nadler; Elena V Galkina

doi:10.1093/ehjopen/oeac028

The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction

Eur Heart J Open. 2022 Apr 20;2(3):oeac028. doi: 10.1093/ehjopen/oeac028. eCollection 2022 May.

Authors

William Coles Keeter¹, Nigeste M Carter², Jerry L Nadler³, Elena V Galkina¹

Affiliations

¹ Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Rd, LH3180, Norfolk 23507, VA, USA.
² Department of Pharmacology and Toxicology & Toxicology, Virginia Commonwealth University, Richmond 23298, VA, USA.
³ Department of Medicine and Pharmacology, New York Medical College, Valhalla 10595, NY, USA.

Abstract

Aims: Mouse models with genetic modifications are required to investigate atherogenesis and associated metabolic syndrome. Adeno-associated virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) induces hyperlipidaemia and promotes atherosclerosis in C57BL/6 mice. We aimed to assess whether AAV8-PCSK9-injected C57BL/6 mice fed high-fat diet with added cholesterol (HFD-C) would serve as a model of combined metabolic syndrome and atherosclerosis.

Methods and results: C57BL/6 mice received i.v. injection of AAV-PCSK9 and sex- and age-matched Ldlr^-/- and C57BL/6 control mice were placed on HFD-C or chow diet for 20 weeks (B6-PCSK9-HFD-C, Ldlr^-/- HFD-C, B6-HFD-C, and B6-Chow, respectively). High-fat diet with added cholesterol feeding led to insulin resistance and impaired glucose clearance in B6-PCSK9-HFD-C mice compared with B6-Chow controls. This decrease in metabolic health in B6-PCSK9-HFD-C mice as well as the development of atherosclerosis was similar to Ldlr^-/- HFD-C mice. Importantly, HFD-C feeding induced pancreatic islet hyperplasia in B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls. In line with alterations in the metabolic phenotype, there was an increase in the number of pro-inflammatory Ly6C^high/med monocytes within the adipose tissues of B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls.

Conclusion: High-fat diet with added cholesterol-fed AAV-PCSK9-injected C57BL/6 mice can serve as a useful model of integrated metabolic syndrome and atherosclerosis that does not require genetic manipulations.

Keywords: Atherosclerosis; Hypercholesterolaemia; Inflammation; Metabolic syndrome; Obesity.

Abstract

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