Lipoprotein(a), Endothelial Dysfunction and Cardiovascular Disease

Q: What is the clinical evidence from this study?

Study design: Review. Population: Atherosclerotic cardiovascular disease (ASCVD) and endothelial dysfunction. Intervention: Lipoprotein(a) (Lp(a)) and Lp(a)-lowering therapies. Primary outcome: Endothelial dysfunction and atherosclerotic cardiovascular disease progression.

Q: What does this research mean for the field?

Elevated lipoprotein(a) drives atherosclerotic cardiovascular disease progression primarily by penetrating the vascular endothelium and inducing endothelial dysfunction through oxidative stress, inflammation, and impaired nitric oxide bioavailability. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Xianghui Zhou; Xiyuan Fang; Xin Zhou; Zhao Zhang; Yu Hu; Cheng Zhipeng

doi:10.1111/jcmm.71426

November 1, 2026Journal of Cellular and Molecular MedicineOpen Access

Lipoprotein(a), Endothelial Dysfunction and Cardiovascular Disease

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Key result

Lp(a) drives endothelial dysfunction and atherosclerosis by inducing vascular inflammation, oxidative stress, and pyroptosis.

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Why the study?

The molecular mechanisms underlying Lp(a)-mediated endothelial injury and the extent to which Lp(a) lowering improves endothelial function remain incompletely defined.

Key Points

Consolidate scientific understanding of how elevated lipoprotein(a) levels induce endothelial dysfunction and accelerate atherosclerotic cardiovascular disease progression.
Narrative review synthesizing molecular, cellular, and clinical literature on lipoprotein(a) synthesis, metabolism, and vascular interaction.
Evaluation of endothelial transcytosis mechanisms, oxidative modification pathways, and pro-inflammatory signaling cascades.
Lipoprotein(a) crosses the endothelial barrier potentially via ALK1/CAV1 transcytosis and activates NF-κB and MAPK pathways, promoting inflammatory cytokine release including IL-1β, IL-6, IL-8, TNF-α, and MCP-1.
Oxidative modification of subendothelial lipoprotein(a) generates reactive oxygen species, impairs nitric oxide bioavailability, and triggers endothelial injury via pyroptosis and glycolysis.
Currently available lipoprotein(a)-lowering therapies modulate endothelial cell function, though the precise molecular pathways and full clinical benefits remain to be established.

Structured PICO

P

Population

Patients with elevated Lipoprotein(a) (Lp(a)) levels and atherosclerotic cardiovascular disease (ASCVD), as well as preclinical endothelial cell models (e.g., HCAECs, HUVECs)

I

Intervention

Elevated Lipoprotein(a) (Lp(a)) exposure and Lp(a)-lowering or endothelial-modulating strategies (oestrogen-based therapy, nicotinic acid, eicosapentaenoic acid, PCSK9 inhibitors [evolocumab, alirocumab], lipoprotein apheresis, antisense oligonucleotides, siRNA)

O

Outcome

Endothelial dysfunction (characterized by transcytosis, subendothelial retention, NF-κB/MAPK inflammatory signalling, eNOS uncoupling, oxidative stress, pyroptosis, and glycolytic reprogramming) and ASCVD progressionsurrogate

This review consolidates the mechanistic pathways linking elevated Lp(a) to vascular endothelial dysfunction and summarizes the endothelial effects of current and emerging Lp(a)-lowering therapies.

Limitations

The exact molecular mechanisms underlying Lp(a)-mediated endothelial injury remain incompletely defined.
The extent to which Lp(a) lowering improves endothelial function in humans remains unclear.
Current Lp(a) detection methods lack standardization across varied racial and ethnic populations.
No drug therapy specifically targeting Lp(a) has been approved for clinical use yet.
Molecular mechanisms underlying Lp(a)-mediated endothelial injury such as intracellular transcriptional regulation and signal transduction remain unclear
The extent to which profound Lp(a) reduction restores endothelial function and predicts cardiovascular benefit is not yet established
Lack of standardized Lp(a) measurement assays and reference materials across different populations
Currently available therapies that lower Lp(a) have limitations, such as modest efficacy, transient effects, or adverse reactions, and no specific Lp(a)-targeting drug is yet approved

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Implication

Consolidates Lp(a) endothelial mechanisms in atherosclerosis; leaves open clinical translation of lowering therapies.

Abstract

Lipoprotein(a) (Lp(a)) is a particle similar to low-density lipoprotein cholesterol and is associated with apolipoprotein (A). High Lp(a) levels are a genetic, independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Endothelial cells, which form the continuous lining of the cardiovascular system, are crucial for vascular function and represent the primary target of Lp(a)-mediated injury. Lp(a) penetrates the endothelial barrier and undergoes oxidative modification, triggering endothelial dysfunction, which is characterized by inflammation, oxidative stress and impaired nitric oxide bioavailability. These disruptions promote monocyte recruitment, foam cell formation and atherosclerosis development. Currently, various drugs that can reduce Lp(a) levels are also involved in regulating endothelial cell function, ultimately reducing the risk of ASCVD. However, the molecular mechanisms underlying Lp(a)-mediated endothelial injury and the extent to which Lp(a) lowering improves endothelial function remain incompletely defined. Clarifying these issues may inform cardiovascular risk stratification and the clinical development of Lp(a)-targeted therapies. This review seeks to consolidate the understanding of the link between Lp(a) levels and endothelial dysfunction, highlighting its pivotal role in cardiovascular disease progression.

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Cite This Study

Zhou et al. (2026) conducted a review in Atherosclerotic cardiovascular disease (ASCVD) and endothelial dysfunction. Lipoprotein(a) (Lp(a)) and Lp(a)-lowering therapies was evaluated on Endothelial dysfunction and atherosclerotic cardiovascular disease progression. Lipoprotein(a) penetrates the endothelial barrier to induce inflammation, oxidative stress, eNOS uncoupling, pyroptosis, and glycolysis, driving endothelial dysfunction and atherosclerosis.

synapsesocial.com/papers/6aefbd5d50d2071ffda4bce1 https://doi.org/10.1111/jcmm.71426

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Lipoprotein(a), Endothelial Dysfunction and Cardiovascular Disease

Figures

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Lipoprotein(a), Endothelial Dysfunction and Cardiovascular Disease

Figures

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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