Review Article

Presumed Mechanisms Underlying Lipoprotein(a)-caused Atherosclerosis

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Abstract

Lipoprotein(a) (Lp(a)) is increasingly recognised as an independent and causal risk factor for atherosclerotic cardiovascular disease. Although the underlying mechanisms remain incompletely defined, evidence supports a multifactorial role for Lp(a) in atherogenesis. Lp(a) contributes to endothelial dysfunction, promotes vascular inflammation and enhances lipid retention and oxidation within the arterial wall. These changes drive foam cell formation and smooth muscle cell activation, hallmarks of early plaque development. In addition, Lp(a) exerts prothrombotic effects through structural homology with plasminogen, interfering with fibrinolysis and promoting thrombosis, which may increase the risk of plaque rupture and acute events. Collectively, these overlapping mechanisms underscore the unique contribution of Lp(a) to both the development and progression of atherosclerosis. As novel targeting therapies emerge, a deeper understanding of Lp(a) biology will be essential for translating these insights into clinical benefit.

Keywords

Lipoprotein(a), atherosclerosis, coronary artery disease, cardiovascular risk,

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DOI: https://doi.org/10.15420/ecr.2025.66

Disclosure: AF and LS are supported by institutional grants from Amgen and Philips. MG has received consultant fees/honoraria from New Amsterdam, Bayer and Medtronic, and has received research grants from the Congressionally Directed Medical Research Program–Department of Defense (WARRIOR study).

Acknowledgements: The authors acknowledge the use of AI assistance in creating the central illustration.

Correspondence: Martha Gulati, The Davis Women’s Heart Center, DeBakey Heart & Vascular Institute, Department of Cardiology, Houston Medical Center, 6550 Fannin St, Smith Tower, Suite 1901, Houston, TX 77030, US. E: mgulatu@houstonmethodist.org

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Atherosclerosis remains the leading contributor to global morbidity and mortality.1 Current prevention strategies are based on traditional risk factors, such as LDL cholesterol, hypertension, obesity, smoking and diabetes. However, after optimal treatment of traditional risk factors, many studies have shown that the persistent residual risk remains substantial. For example, residual risk remained substantial among optimally treated secondary prevention patients in both the ODYSSEY and FOURIER trials, underscoring the need to elucidate novel causal pathways, with lipoprotein(a) (Lp(a)) emerging as a likely key contributor.2,3 Lp(a), a complex lipoprotein particle, has emerged as a genetically determined and independent risk factor for atherosclerotic cardiovascular disease, with the strongest correlation with coronary artery disease and more modest correlations with ischaemic stroke and peripheral artery disease.4 Lp(a) was first described in 1963 by Kare Berg, with subsequent studies demonstrating that Lp(a) is highly heritable, with plasma concentrations largely determined by genetic variation in the LPA gene.5–7

Central Illustration: Lipoprotein(a) in Atherosclerosis: Proatherogenic, Proinflammatory and Antithrombotic Pathways

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Unlike other apolipoprotein B (apoB)-containing lipoproteins, Lp(a) consists of an LDL variant that is covalently bound to apolipoprotein(a) (apo(a)), a glycoprotein structurally similar to plasminogen (Figure 1 ).8,9 This distinctive structure confers a complex pathogenic profile to Lp(a) characterised by proatherogenic, proinflammatory and antifibrinolytic properties. Given these diverse and overlapping mechanisms, Lp(a) plays a central role in the phenotypic transformation of vascular cells towards a proinflammatory state and in the development and progression of lipid-rich atherosclerotic plaque. Although epidemiological and genetic studies strongly support a causal role for Lp(a) in atherosclerotic cardiovascular disease, the underlying mechanisms remain incompletely defined.8 This review synthesises current evidence on the pathophysiological processes by which Lp(a) contributes to atherogenesis.

Figure 1: Structural Features of Apolipoprotein(a) and its Homology with Plasminogen

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Structure and Biological Properties of Lipoprotein(a)

Lipoprotein(a)

Lp(a) is structurally similar to LDL, consisting of a lipid-rich core encased in a phospholipid monolayer and containing a single apoB-100 molecule. The defining distinction from LDL is the presence of apo(a), a heavily glycosylated protein covalently attached to apoB-100 through a disulfide bond (Figure 2).8 This unique structural feature confers distinct biophysical properties compared to LDL. The circulating Lp(a) concentrations is predominantly determined by its rate of hepatic synthesis.10 Although the pathways for Lp(a) clearance are not fully understood, current evidence suggests predominant hepatic uptake, with minor contributions of the kidney, spleen and skeletal muscle.11

Apolipoprotein(a)

Apo(a) exhibits structural homology with plasminogen, due to the presence of kringle domains (K), a looped protein of approximately 80 amino acids stabilised by three disulfide bonds. These K domains contain lysine binding site (LBS), which enables the protein to recognise and attach to lysine residues on fibrin, cell-surface receptors and other ligands. This interaction is critical for mediating processes such as binding to the extracellular matrix, facilitating lipoprotein retention and interfering with fibrinolysis. Plasminogen contains five kringle types (KI–KV), whereas apo(a) includes a single KV domain and 10 distinct KIV types, each with their own specific amino acid composition. The LBS vary in affinity across kringle types. In plasminogen, the highest LBS affinity is found in KI, followed by KIV and KV.12 In contrast, in apo(a), KIV type 10 (KIV10) displays the strongest lysine-binding affinity, exceeding that of KIV types 5–8 (Figure 1 ).13,14

A unique feature of apo(a) is the variable number of KIV type 2 (KIV2) repeats, ranging from 1 to over 40 copies, which contributes to the heterogeneity of apo(a) isoform size (Figure 2). Shorter apo(a) isoforms, characterised by fewer KIV2 repeats, are produced at a higher rate by hepatocytes and are associated with elevated circulating Lp(a) levels.15,16 These smaller isoforms demonstrate enhanced binding to oxidised phospholipids (OxPLs), greater inhibition of plasminogen activation and increased prothrombotic activity.17–19 They also show a higher propensity to deposit within the arterial wall.20 Furthermore, smaller apo(a) exhibits synergistic proatherogenic effects when combined with dense LDL and oxidised LDL particles.21

Figure 2: Structural and Compositional Characteristics of Lipoprotein(a) LDL and HDL

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Lp(a) levels vary widely among individuals, with up to 90% of this variability attributed to genetic factors, particularly the LPA gene located on chromosome 6q26–27.10 This gene, which encodes apo(a), shares approximately 70% sequence homology with the plasminogen gene.22 Polymorphisms in the LPA gene, especially copy number variants of the KIV2 domain, are responsible for interindividual and interethnic variability in Lp(a).6 However, other genes beyond the LPA gene may influence Lp(a) regulation, although their contributions remain less clearly defined.23

Proatherogenic Mechanisms

Endothelial Dysfunction

One of the key mechanisms by which Lp(a) promotes atherosclerosis is through its ability to deliver cholesterol to the endothelium of the arterial wall. Lp(a)-induced endothelial dysfunction represents a critical early step in the initiation of atherosclerosis and is both a marker and a mediator of cardiovascular risk. Apo(a) interacts with endothelial cells and promotes cytoskeletal remodelling via activation of the Rho/Rho-kinase signalling pathway, leading to increased phosphorylation of myosin light chain, formation of central actin stress fibres and disruption of vascular endothelial (VE) cadherin-mediated adherens junctions.24 The consequent loss of endothelial integrity leads to increased vascular permeability, facilitating the infiltration of lipoproteins and monocytes into the subendothelial space (Figure 3).

Within the vessel wall, Lp(a) is localised predominantly in the extracellular matrix of the intima and subintima.25 Notably, its accumulation exceeds that of LDL, as evidenced by higher levels of apo(a) relative to apoB-100 in early atherosclerotic lesions, and Lp(a) has been reported to be up to sixfold higher more atherogenic than LDL.26–28 Lp(a) retention is mediated both by its lipoprotein structure and the presence of lysine-binding domains within apo(a).13 These domains are critical for binding to extracellular matrix components. Supporting this, transgenic mouse models with mutations in the KIV10 LBS of apo(a) exhibit significantly reduced arterial deposition of Lp(a), highlighting the importance of these molecular interactions in mediating the atherogenic potential of Lp(a).29

Vascular Smooth Muscle Cell Proliferation and Migration

Beyond its effect on endothelial cells, Lp(a) influences vascular remodelling by activating vascular smooth muscle cells (VSMCs). Under normal physiological conditions, VSMCs exhibit a contractile phenotype that supports vessel stability. However, inflammatory and pro-oxidative conditions, particularly the presence of OxPLs associated with Lp(a), trigger a phenotypic shift towards a synthetic state. This state is characterised by enhanced proliferation, migration and extracellular matrix synthesis. Apo(a) can inhibit transforming growth factor-β signalling, a pathway essential for preserving the quiescent VSMC phenotype, thereby facilitating VSMC activation.30 Moreover, OxPLs on Lp(a) stimulate proliferative and migratory responses through several molecular pathways, including nuclear factor (NF)-κB activation and the induction of Krüppel-like factor 4.31,32 In vitro studies have also demonstrated that OxPLs promote osteogenic gene expression in VSMCs, leading to calcification.32 Collectively, these changes drive the accumulation of VSMCs within the intima layer, where they contribute to the formation of the fibrous cap of atherosclerotic plaques (Figure 3).

Figure 3: Proatherogenic Mechanisms of Lipoprotein(A)

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Oxidative Stress

Lp(a) contributes significantly to oxidative stress within the vascular wall, primarily due to its high content of OxPLs associated with apo(a), through KIV10 (Figure 1).33,34 These OxPLs are potent inducers of reactive oxygen species (ROS) production in both endothelial cells and macrophages. The resulting oxidative stress leads to lipid peroxidation, protein modification and DNA damage, thereby contributing to endothelial dysfunction and vascular inflammation. In endothelial cells, ROS reduce nitric oxide availability by both scavenging nitric oxide directly and reducing endothelial nitric oxide synthase activity, ultimately impairing vasodilation and enhancing leukocyte adhesion. In macrophages, ROS promote foam cell formation and trigger apoptotic signalling, further propagating inflammatory responses within the atherosclerotic plaque.35,36

Impaired Clearance and Arterial Retention

The mechanisms and receptor pathways responsible for the plasma clearance of Lp(a) remain incompletely defined.37 Although Lp(a) shares structural similarities with LDL through its apoB-100 component, it is metabolised through distinct pathways that are not primarily dependent on hepatic LDL receptor (LDLR).38 Evidence from animal studies supports LDLR as not a primary mediator of Lp(a) clearance. Although transgenic mice with hepatic overexpression of LDLR exhibit modest reductions in Lp(a) levels, genetic deletion of LDLR does not affect Lp(a) turnover compared with wild-type controls.39,40 A recent analysis from the UK Biobank initially suggested that individuals carrying familial hypercholesterolaemia (FH)-associated LDLR variants exhibited higher Lp(a) levels.41 However, this association was confounded by enrichment of the rs10455872 variant in the LPA gene, which is strongly linked to elevated Lp(a). When this single nucleotide polymorphism was accounted for, Lp(a) concentrations were comparable between individuals with and without FH.41 Similar results were reported by Rader et al. in a cohort of homozygous FH patients.42 Several alternative receptors have been proposed as potential mediators of Lp(a) clearance, including LDLR-related proteins (LRPs), such as LRP1 and LRP2 (megalin), scavenger receptor class B type I and various plasminogen receptors (i.e. plasminogen receptor with a C-terminal lysine [PLGRKT]). PLGRKT has been shown to enhance Lp(a) uptake in hepatic and fibroblast cells, whereas silencing of this receptor leads to a marked reduction in Lp(a) internalisation.43–45 Conversely, other receptors, including the very low-density lipoprotein receptor, LDL receptor-related protein-8, the asialoglycoprotein receptor and sortilin, have shown no significant effect on Lp(a) clearance in experimental models.40,46,47 Despite these observations, the physiological relevance of each pathway remains incompletely understood.

Pharmacological data further reinforce the limited role of LDLR in Lp(a) clearance. Statins, which lower LDL cholesterol by upregulating LDLR expression in hepatocytes, were initially believed to have no effect on Lp(a) levels.48 However, more recent data indicate that statins modestly increase Lp(a), providing additional indirect evidence against LDLR involvement.49 Interestingly, Yahya et al. demonstrated that the effect of statins on Lp(a) is particularly pronounced in individuals with small apo(a) isoforms (≤22 KIV repeats), whereas individuals with larger apo(a) isoforms experienced no significant change in Lp(a) levels with statins.50

Foam Cell Formation

Foam cells (lipid-laden macrophages) are a hallmark of early atherosclerotic plaques (Figure 3). Lp(a) contributes to foam cell formation through both lipid delivery and proinflammatory signalling. Once Lp(a) infiltrates the intimal layer of the vessel wall, it undergoes oxidative modification, with development of OxPLs. These OxPLs activate innate immune receptors on macrophages, such as CD36 and toll-like receptor 2, leading to their uptake and activation.35,51 This process promotes the accumulation of cholesteryl esters within macrophages, facilitating their transformation into foam cells. The OxPLs bound to Lp(a) further enhance lipid accumulation and simultaneously drive the secretion of proinflammatory cytokines, including interleukin (IL)-8 and I-309, thereby amplifying monocyte recruitment and inflammatory signalling. Notably, Lp(a) carries the majority of OxPLs present in human plasma lipoproteins, highlighting its key role as a carrier and reservoir of these bioactive lipids.52 In addition to driving foam cell formation, Lp(a) promotes macrophage apoptosis, particularly under conditions of endoplasmic reticulum stress. This process, also mediated through CD36 and Toll-like receptors, contributes to necrotic core expansion and increases plaque vulnerability. Foam cells further exacerbate lesion instability by secreting matrix metalloproteinases that degrade the extracellular matrix, weakening the fibrous cap and predisposing plaques to rupture and thrombotic events.35,53

Proinflammatory Mechanisms of Lipoprotein a in Atherosclerosis

Monocyte Recruitment and Endothelial Activation

Lp(a) enhances monocyte recruitment via both endothelial-dependent and -independent mechanisms. Lp(a) upregulates adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin on endothelial cells, facilitating leukocyte adhesion and transmigration.35,54 In addition, Lp(a) stimulates the release of chemokines, such as monocyte chemoattractant protein-1 and I-309, which support monocyte migration into the arterial wall.55,56 Direct interactions between apo(a) and the β2-integrin MAC-1 further promote monocyte adhesion, in part through NF-κB and autotaxin signalling pathways (Figure 4).55,57

Macrophage Activation and Cytokine Secretion

Once monocytes infiltrate the intima, Lp(a)-related signals drive their differentiation into macrophages. Apo(a) favours polarisation towards a proinflammatory macrophage M1 phenotype, characterised by secretion of cytokines such as IL-1β, tumour necrosis factor-α and IL-6, and chemokines like CXCL10, which, in turn, stimulate T helper 1 cells and natural killer cells.58–60 These proinflammatory macrophages perpetuate immune cell recruitment and amplify local inflammation.

Lp(a), particularly via its C-terminal region (comprising KV and protease-like domain), stimulates IL-8 release from macrophages, promoting neutrophil infiltration (Figure 4).58,61,62 This response is further potentiated by OxPLs bound to the LBS within the KIV10 domain of apo(a), highlighting the cooperative contribution of both regions to the proinflammatory activity of Lp(a).33,51

Systemic Inflammatory Signalling

Lp(a) plays a dual role in inflammation, acting both as a driver and a target of inflammatory signalling. Several cytokines, including IL-6, IL-4, IL-13, tumour necrosis factor-α and transforming growth factor-β, can regulate LPA gene expression at the transcriptional level, with IL-6 exerting a particularly strong stimulatory effect.63–65 However, Lp(a) also contributes to vascular inflammation by inducing endothelial activation, promoting leukocyte adhesion and enhancing cytokine secretion. Consistently, individuals with elevated Lp(a) levels show increased arterial inflammation, as demonstrated by 18F-fluorodeoxyglucose PET/CT imaging and pericoronary attenuation by CT.66,67 The reciprocal amplification between IL-6-mediated LPA gene expression and Lp(a)-induced inflammatory signalling may help explain persistent Lp(a) elevation in chronic inflammatory diseases and its contribution to cardiovascular risk.68

Prothrombotic and Antifibrinolytic Effects

Inhibition of Plasminogen Activation

One of the most-characterised antifibrinolytic actions of Lp(a) is its ability to compete with plasminogen for binding to lysine residues on fibrin (Figure 1 ).69,70 Apo(a) contains a Ser-His-Asp catalytic triad typical of proteases, but it is enzymatically inactive due to an Arg-to-Ser substitution at the activation cleavage site in plasminogen.71 This lack of catalytic function, combined with its structural mimicry to plasminogen, enables apo(a) to compete with plasminogen for binding to lysine residues on fibrin, thereby reducing the activation of plasminogen to plasmin by tissue plasminogen activator.69,72 However, despite these observations, definitive in vivo evidence demonstrating the clinical impact of Lp(a)-induced impairment of fibrinolysis remains limited and direct confirmation of its prothrombotic role in human studies is still lacking (Figure 4).69,73

Figure 4: Proinflammatory and Prothrombotic Pathways Mediated by Lipoprotein(a)

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Interaction with Plasminogen Activator Inhibitor-1

Lp(a) may further contribute to a prothrombotic state by modulating the expression and activity of plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator. Elevated Lp(a) levels have been associated with higher concentrations of PAI-1, potentially impairing fibrinolysis.74 In vitro studies further demonstrate that apo(a) can stimulate PAI-1 production in endothelial cells, a response likely mediated by oxidative stress and activation of NF-κB signalling pathways.75

Inhibition of Tissue Factor Pathway Inhibitor

Apo(a) also interferes with endogenous anticoagulant mechanisms. Specifically, apo(a) directly binds to lysine residues of tissue factor pathway inhibitor (TFPI), thereby diminishing the ability of TFPI to suppress coagulation via inhibition of Factor Xa and the tissue factor–Factor VIIa complex. This interaction impairs the regulatory role of TFPI, promoting thrombin generation.69 Experimental data demonstrate that Lp(a) reduces TFPI activity in a dose-dependent manner, with the K domains of apo(a) implicated in mediating this effect through lysine-dependent interactions.76 Considering that apo(a) isoforms with defective LBS in KIV10 exhibited reduced affinity for the arterial wall and less atherogenesis, this finding reinforces the critical role of these lysine-mediated interactions.29

Effects on Fibrin Clot Structures

Beyond impairing fibrinolysis, Lp(a) influences fibrin clot structure, even though the exact mechanism is not fully understood. Studies have shown that clots formed in the presence of high Lp(a) levels have a denser, more tightly packed fibrin network. These clots exhibit decreased permeability and are significantly more resistant to plasmin-mediated lysis, further exacerbating thrombotic risk.77,78

Lipoprotein a and Plaque Vulnerability

Lp(a) plays a central role in the development and progression of atherosclerosis and contributes to the structural vulnerability of atherosclerotic plaques. Features of unstable plaques, such as an enlarged lipid-rich necrotic core, thin fibrous cap and extensive inflammatory cell infiltration, may be amplified by Lp(a)-mediated biological mechanisms (Figure 3). Long-term prospective studies on serial coronary CT angiography provide strong evidence of this association. High Lp(a) concentrations were associated with higher progression of total plaque burden, greater low-attenuation non-calcified plaque volume (a surrogate marker of necrotic core) and heightened pericoronary adipose tissue inflammation.79 These imaging findings indicate an active inflammatory state and identify the presence of high-risk plaque phenotypes, underscoring the role of Lp(a) in coronary artery disease. Moreover, in patients with advanced stable coronary artery disease, elevated Lp(a) levels have been associated with rapid expansion of the necrotic core, further supporting the role of Lp(a) in cardiovascular risk assessment and supporting its potential as a therapeutic target.80

Conclusion

The proatherogenic, proinflammatory and antifibrinolytic properties of Lp(a) are mainly attributed to its apo(a) component and to the associated OxPLs. Lp(a) promotes endothelial dysfunction, vascular inflammation and foam cell formation and impairs fibrinolysis, driving both plaque development and thrombotic risk. Despite advances in our understanding of its clinical relevance and therapeutic targeting, key questions about the physiological role of Lp(a), its metabolism and optimal therapies remain to be fully elucidated. As novel Lp(a)-lowering treatments emerge, deepening our knowledge of their mechanisms of action is crucial for improving cardiovascular outcomes.

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