Lipoprotein(a) associates with circulating annexin a1-positive extracellular vesicles linked to arterial calcification
P Haider, J Bernhard, F Wollmann, W Speidl, C Hengstenberg, P Hohensinner, K KrychtiukAbstract
Background/Introduction
Lipoprotein(a) (Lp(a)) is a genetically determined and independent cardiovascular risk factor strongly associated with coronary artery disease and calcific aortic valve disease. Concentrations above 125–190 nmol/L confer markedly increased lifetime risk. The biological mechanisms linking Lp(a) to arterial calcification remain insufficiently defined. Extracellular vesicles (EVs) released from activated immune and vascular cells contribute to microcalcification by providing phosphatidylserine-rich surfaces and calcification-promoting proteins. Annexin A1 (ANXA1)-positive EVs have been described as pro-calcifying vesicles in vitro and have been detected within calcified vascular and valvular tissue, suggesting a mechanistic role in mineral deposition.
Purpose
To investigate whether circulating Lp(a) levels are associated with ANXA1-positive calcifying EVs in human and to explore their potential role in arterial calcification.
Methods
In a cohort of 20 statin-naïve individuals (10 female, 10 male) from a lipid outpatients clinic with comparable low-density lipoprotein cholesterol but increasing Lp(a) concentrations, EVs were isolated from citrate plasma by ultracentrifugation. Flow cytometry optimised for small particles (160–500 nm) was performed using antibodies against ANXA1, CD29 and CD63. Total and relative ANXA1/CD29-positive EV events were quantified. Linear regression analyses assessed associations between Lp(a) levels and EV counts. Patients were additionally stratified by Lp(a) <190 versus ≥190 nmol/L.
Results
Lp(a) levels correlated significantly with total ANXA1-positive EV counts (R²=0.3311, p=0.0125). A stronger association was observed for relative ANXA1-positive EV abundance (R²=0.4551, p=0.0021). Patients with very high Lp(a) concentrations (~500 nmol/L) exhibited the highest EV levels. Stratification by the clinically relevant threshold of 190 nmol/L demonstrated significantly higher ANXA1-positive EV counts in individuals with Lp(a) ≥190 nmol/L compared with those below this threshold (p<0.05). These data indicate a dose–response relationship between circulating Lp(a) and calcifying EV burden.
Conclusion(s)
Elevated Lp(a) is associated with increased circulating ANXA1-positive calcifying EVs in humans. This mechanism may represent a pathophysiological link between high Lp(a) concentrations and arterial calcification. Targeting Lp(a)-driven EV release could constitute a novel preventive strategy to attenuate calcific cardiovascular disease.Data