Lipoprotein(a)-The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation.

Sabina Ugovšek,Miran Šebeštjen

doi:10.3390/biom12010026

Abstract

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients.

Highlights

Lipoprotein(a) (Lp(a)) is a complex plasma protein that consist of low-density lipoprotein (LDL) cholesterol and apolipoprotein B-100 linked to the plasminogen-like apolipoprotein(a) (apo(a)) via a disulfide bond
We have previously shown that patients with familial hyperholesterolemia who had survived myocardial infarction at a young age had significanly decreased fibrinolytic activity, as shown by increased plasminogen activator inhibitor-1 (PAI-1) antigen and activity, and increased t-PA antigen, compared to those without myocardial infarction [72]
Similar findings were observed with inclisiran, a small interfering RNA

Summary

Introduction

Lipoprotein(a) (Lp(a)) is a complex plasma protein that consist of low-density lipoprotein (LDL) cholesterol and apolipoprotein B-100 (apoB) linked to the plasminogen-like apolipoprotein(a) (apo(a)) via a disulfide bond. Lp(a) levels are genetically determined by the LPA gene and they vary among individuals from ≤0.2 to ≥250 mg/dL, within a single individual, Lp(a) levels are stable throughout life [1,2]. The LPA gene is located on chromosome 6q26–q27 and it encodes the highly glycosylated hydrophilic apo(a) [3,4]. Apo(a) shows high amino-acid sequence homology to serine protease plasminogen [3]. Apo(a) contains a protease-like domain and two tri-loop structures known as ‘kringles’. (KIV, KV) [1,3], and the KIV domain has 10 types [3].

Objectives

Findings

Conclusion