Abstract
Background: Extracellular vesicles (EV) concentration is generally increased in patients with cardiovascular diseases, although the protective role of EVs in atherosclerosis has been reported. Among the specific cargo of EVs, miRNAs contribute to different stages of atherosclerosis. Aim of the present report has been to investigate, in individuals with obesity, the interplay among EVs derived from cells relevant for the atherosclerotic process (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils), their miRNA content and proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of low-density lipoprotein receptor (LDLR).Methods and Results: EVs have been isolated from 936 individuals with obesity (body mass index = 33.6 ± 5.6 Kg/m2) and a raised cardiovascular risk (e.g., LDL-C = 131.6 ± 36.4 mg/dL, HOMA-IR = 3.1, and roughly 50% on anti-hypertensive medications). PCSK9 levels were negatively associated with EV count in the range 150–400 nm and with those derived from macrophages (CD14+), endothelium (CD105+), and neutrophils (CD66+). The association between PCSK9 and platelet-derived EVs (CD61+) was modified by platelet counts. PCSK9 was significantly associated with five EV-derived miRNAs (hsa-miRNA−362−5p,−150,−1244,−520b-3p,−638). Toll-like receptor 4 and estrogen receptor 1 were targeted by all five miRNAs and LDLR by four. The effect on LDLR expression is mainly driven by hsa-miR-150. Considering the implication of EV in atherosclerosis onset and progression, our findings show a potential role of PCSK9 to regulate EV-derived miRNAs, especially those involved in inflammation and expression of low-density lipoprotein receptor (LDLR) receptor.
Highlights
Atherosclerosis is a leading cause of morbidity and mortality worldwide [1]
Considering that extracellular vesicles (EVs) are vehicles of bioactive molecules which influence the intertwined relationship among players of the atherosclerotic process, the present study aims to investigate the interplay among proprotein convertase subtilisin/kexin type 9 (PCSK9), EVs derived from cells relevant for the atherosclerotic process and their miRNA content in a population of subjects with obesity
Since we previously reported the effect of PM10 exposure on EVs release, this variable was used as a covariate in the model
Summary
Atherosclerosis is a leading cause of morbidity and mortality worldwide [1]. Vascular diseases associated with atherosclerosis include ischemic heart disease, ischemic stroke, and peripheral artery disease. Atherosclerosis is a complex disorder, and many components of the vascular, metabolic, and immune systems are involved in this process It is a progressive inflammatory disease affecting large and medium-sized blood vessels by triggering the formation of a plaque in the vessel wall [2]. It is generally thought that EV concentration is increased in patients with cardiovascular diseases [3, 4], and a large amount of EVs has been observed within the atherosclerotic plaque [5], the protective role of EVs in atherosclerosis has been reported [6]. Extracellular vesicles (EV) concentration is generally increased in patients with cardiovascular diseases, the protective role of EVs in atherosclerosis has been reported. Aim of the present report has been to investigate, in individuals with obesity, the interplay among EVs derived from cells relevant for the atherosclerotic process (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils), their miRNA content and proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of low-density lipoprotein receptor (LDLR)
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