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 × 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-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.
Highlights
Hypercholesterolemia is a major risk factor for cardiovascular and cerebrovascular diseases and is associated with high mortality and morbidity [1]
The mPCSK9-associated virus (AAV)-injected mice on the standard diet had a 297-fold higher plasma mouse protein convertase subtilisin/kexin type 9 (PCSK9) levels compared with the control AAV-injected mice on the standard diet, and 280fold increased PCSK9 plasma levels compared with the controlAAV-injected mice on the high-fat diet (HFD)
PCSK9 levels were significantly higher in HFD-fed mice compared with standard diet-fed mice, hinting at a potential role that the diet may have exerted in the elevation of PCSK9 levels
Summary
Hypercholesterolemia is a major risk factor for cardiovascular and cerebrovascular diseases and is associated with high mortality and morbidity [1]. High lipoprotein blood levels promote atherosclerosis, which involves plaque formation in arteries by inflammation, lipid accumulation, cell death, and fibrosis [2]. A release and activation of blood cells, e.g., monocytes, macrophages, platelets, endothelial cells, and T lymphocytes, together with an altered production of adhesion molecules and integrins leads to an imbalance between pro-coagulant and anticoagulant molecules, an increased production of cytokines (e.g., interleukin-1β, interleukin-4, interleukin-6, and interleukin-10, tumor necrosis factor, and interferons), and an interaction of inflammatory cells with the vessel wall, promoting vascular inflammation and thrombosis [7, 8]. Increased levels of inflammatory and coagulation factors in the circulation have been shown to be associated with an increased risk of myocardial infarction and ischemic stroke [9,10,11]. A better understanding of the role of hypercholesterolemiamediated thromboinflammation is warranted
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