Comparative Analysis of Atherogenic Lipoproteins L5 and Lp(a) in Atherosclerotic Cardiovascular Disease

Abstract

Purpose of review: Low-density lipoprotein (LDL) poses a risk for atherosclerotic cardiovascular disease (ASCVD). As LDL comprises various subtypes differing in charge, density, and size, understanding their specific impact on ASCVD is crucial. Two highly atherogenic LDL subtypes-electronegative LDL (L5) and Lp(a)-induce vascular cell apoptosis and atherosclerotic changes independent of plasma cholesterol levels, and their mechanisms warrant further investigation. Here, we have compared the roles of L5 and Lp(a) in the development of ASCVD.

Recent findings: Lp(a) tends to accumulate in artery walls, promoting plaque formation and potentially triggering atherosclerosis progression through prothrombotic or antifibrinolytic effects. High Lp(a) levels correlate with calcific aortic stenosis and atherothrombosis risk. L5 can induce endothelial cell apoptosis and increase vascular permeability, inflammation, and atherogenesis, playing a key role in initiating atherosclerosis. Elevated L5 levels in certain high-risk populations may serve as a distinctive predictor of ASCVD. L5 and Lp(a) are both atherogenic lipoproteins contributing to ASCVD through distinct mechanisms. Lp(a) has garnered attention, but equal consideration should be given to L5.

Keywords: Atherogenesis; Atherosclerotic Cardiovascular Disease; Electronegative LDL; L5; Lp(a); Oxidized LDL.

Fig. 1

Schematic representation of the structural components of L1, L5, and Lp(a). Normal LDL is represented by L1 because they have the same chemical structure and function. Apo(a) is noted to be richly associated with oxidized phospholipids, whereas L5 is as minimally oxidized as L1, if any. Unlike L1, Lp(a) and L5 have two disulfide-linked apolipoproteins: apoB100 and apo(a). L5 has a lipid core composed of greater amounts of cholesteryl ester than triacylglycerols. Apo, apolipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a)

Fig 2

Schematic representation showing the contribution of L1, L5, and Lp(a) to atherosclerosis. (a) Under normal circumstances, LDLR mediates the uptake of LDL into ECs. The rate of production of oxLDL in the arterial intima in vivo is a function of the concentration of native LDL present. Macrophages are loaded with cholesterol as they take up all oxidized products including oxLDL, oxLp(a), and oxL5. Oxidized-LDL generated either locally or systemically stimulates ECs to express adhesion molecules, including ICAM-1, vascular cell adhesion molecule-1, and E-selectin, which are responsible for the adhesion of blood monocytes. (b) L5 activates ECs via LOX-1 and PAFR, suppressing PI3K/Akt signaling and increasing the release of TNF-α. L5 induces the expression of Bax and Bad, followed by the release of cytochrome c from mitochondria, thereby inducing apoptosis. L5 also augments adhesion between monocytes and ECs. (c) Lp(a) promotes EC damage by inducing mural thrombosis and EC dysfunction, leading to the passage of Lp(a) through the protective endothelial layer. Lp(a) can also activate circulating monocytes and induce monocyte trafficking to the arterial wall. The green arrows show induction/stimulation. Red bars show repression/prevention. Akt, protein kinase B; Bcl2, B cell lymphoma 2; CRP, C-reactive protein; ECs, endothelial cells; eNOS, endothelial nitric oxide synthase; FGF2, fibroblast growth factor 2; FGF2R, fibroblast growth factor 2 receptor; ICAM-1, intercellular adhesion molecule 1; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; Lp(a), lipoprotein(a); oxL5, oxidized L5; oxLDL, oxidized low-density lipoprotein; oxLp(a), oxidized lipoprotein(a); oxPL, oxidized phospholipids; PAFR, platelet-activating factor receptor; PI3K, phosphatidylinositol-3-kinase; PLG, plasminogen; ROS, reactive oxygen species; SMC, smooth muscle cells; TNF-α, tumor necrosis factor alpha; tPA, tissue plasminogen activator; VCAM-1, vascular cell adhesion molecule-1