Key result
Higher PCSK9 levels in obesity linked to ~0.4% lower extracellular vesicle concentration per 10 ng/mL.
Why the study?
The interplay among extracellular vesicles derived from atherosclerosis-relevant cells, their miRNA content, and PCSK9 in individuals with obesity and raised cardiovascular risk was not well understood.
Cross-Sectional (n=936)
No
In adults with obesity, PCSK9 levels are associated with specific extracellular vesicles and their miRNA cargo, suggesting a potential regulatory role in inflammation and LDLR expression.
Answers are grounded in this paper and cite their sources.
Associations in obese adults should not change PCSK9 inhibitor practice; hypothesis-generating for EV-miRNA regulation in atherosclerosis.
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.
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A 2022 study conducted a cross-sectional in Obesity (n=936). PCSK9 levels was evaluated on Total extracellular vesicle (EV) concentration (IRR 0.996, 95% CI 0.992-0.999, p=0.0377). In adults with obesity, higher circulating PCSK9 levels were significantly associated with a decreased total concentration of extracellular vesicles (IRR 0.996 per 10 ng/mL increase).
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