Aggregation Susceptibility of Low-Density Lipoproteins-A Novel Modifiable Biomarker of Cardiovascular Risk.

Katariina Öörni,Petri T Kovanen

doi:10.3390/jcm10081769

Abstract

Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles’ aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied.

Highlights

Strong evidence from epidemiologic, genetic, and clinical studies has shown that lowdensity lipoprotein (LDL) particles are causal agents in atherogenesis, the process causing atherosclerotic cardiovascular disease (ASCVD) [1]
We have shown that the aggregation susceptibility of LDLs is increased in patients stenosis had more aggregation-prone
We only studied the qualities of the SMase substrate without being able to measure the activity of the enzyme in the atherosclerotic coronary artery plaques, mere detection of the presence of highly aggregation-susceptible circulating

Summary

Introduction

Strong evidence from epidemiologic, genetic, and clinical studies has shown that lowdensity lipoprotein (LDL) particles are causal agents in atherogenesis, the process causing atherosclerotic cardiovascular disease (ASCVD) [1]. During atherogenesis, circulating LDL particles enter the subendothelial extracellular space of the arterial wall. In contrast to other peripheral tissues, in which the concentration of LDL particles in the extracellular fluid is only 10% of that in the circulating blood, in the arterial intima, the concentration of LDL particles is about the same as in the circulation—i.e., it is 10-fold higher than in other tissues [2]. The initiation of atherosclerosis is characterized by an extracellular accumulation of small lipid droplets and vesicles that are associated with the extracellular matrix of the intima [10,11]. As reviewed by Öörni and coworkers [8], the analysis of the LDL-like particles isolated from rabbit and human atherosclerotic lesions showed signs of slight modification, whereas the lipid droplets and aggregated particles had features of extensive modification of LDL particles. The visual observations demonstrated the presence of extracellularly located, aggregated and fused particles, and omics analyses of the isolated aggregates suggested that the particles had originated from lipase-modified apoB-containing circulating lipoprotein particles

LDL Particles—The Major Cholesterol Carriers in the Circulation

Potential Mechanisms of Aggregation of LDL Particles in the Arterial Intima

Increased Aggregation

Attempts to Reduce the Aggregation Susceptibility of LDL Particles—From

Findings

Conclusions and Future Directions