Lipoprotein(a), a Lethal Player in Calcific Aortic Valve Disease

Abstract

Calcified aortic valve disease (CAVD) is the most common valvular cardiovascular disease with increasing incidence and mortality. The primary treatment for CAVD is surgical or transcatheter aortic valve replacement and there remains a lack of effective drug treatment. Recently, lipoprotein (a) (Lp(a)) has been considered to play a crucial role in CAVD pathophysiology. Multiple studies have shown that Lp(a) represents an independent risk factor for CAVD. Moreover, Lp(a) mediates the occurrence and development of CAVD by affecting aortic valve endothelial dysfunction, indirectly promoting foam cell formation through oxidized phospholipids (OxPL), inflammation, oxidative stress, and directly promotes valve calcification. However, there is a lack of clinical trials with Lp(a) reduction as a primary endpoint. This review aims to explore the relationship and mechanism between Lp(a) and CAVD, and focuses on the current drugs that can be used as potential therapeutic targets for CAVD.

Keywords: apolipoprotein; autotaxin; calcific aortic valve disease; lipoprotein (a); oxidized phospholipid.

FIGURE 1

Schematic drawing of the structure of Lp(a). Lp(a) consists of LDL-like microparticles, a single apoB100 molecule, and apo(a). Apo(a) is composed of inactive protease P domain and cyclic domain. Heterogeneity in the number of KⅣ type 2 repeats accounts for different apo(a) isoforms. Except KⅣ₂, which has multiple copies, the remaining domains are single copy. KⅤ, kringle ring structure Ⅴ; KⅣ, kringle ring structure IV.

FIGURE 2

Mechanisms of Lp(a)-induced CAVD. Schematic diagram depicts the mechanism of Lp(a)-induced CAVD. The main pathophysiological processes involving Lp(a) in CAVD include endothelial dysfunction, indirect promotion of foam cell formation through OxPL, valvular calcification and so on. Valvular calcification of VICs plays an important role in the occurrence and development of Lp(a)-mediated CAVD. This process of phenotypic transformation is mainly including the Notch signal pathway and NF-κB receptor activator pathway, and is also partially mediated by inflammation, oxidative stress, and the Wnt signal pathway. OxPL, oxidized phospholipids; Lp(a), lipoprotein (a); ATX, autotaxin; Lp-PLA2, lipoprotein-associated phospholipase A2; MCP-1, monocyte-macrophage chemoattractant protein-1; CCR2, C-C chemokine receptor type 2; LPC, lysophosphatidylcholine; LysoPA, lysophosphatidic acid; LPAR, lysophospholipid receptor; GLUT1, glucose transporter type 1; VCAM-1, vascular cell adhesion molecule-1; ICAM1-1, intercellular adhesion molecule-1; IL-6, interleukin 6; BMP-2, bone morphogenetic protein-2; IKKα, IkappaB kinase-alpha; TLR,; Toll-like receptor; VECs, endothelial cells; VICs, valvular interstitial cells.

FIGURE 3

Prospecting treatment of Lp(a)-mediated CAVD. Schematic diagram depicts regulation points for Lp(a) biosynthesis and catabolism (highlighted in blue boxes) as a prospecting treatment target. The green ovals indicate therapeutic agents that have been shown to modulate Lp(a) levels, and potentially Lp(a) pathogenic affects. The prospecting treatment target at which they act is shown with red lines. CETPi, CETP inhibitor; PCSK9i, PCSK9 inhibitor; ASO, antisense oligonucleotides; MTPi, microsome triglyceride transfer protein inhibitor; LRP-1, low-density lipoprotein receptor-related protein-1; SR-B1, scavenger receptor B1; LDLR, low-density lipoprotein receptor; CAVD, calcific aortic valve disease.