REVIEW article
Front. Cardiovasc. Med.
Sec. Lipids in Cardiovascular Disease
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1649759
This article is part of the Research TopicEvidence of Atherogenic Lipoproteins: what we gain from in vitro and in vivo researchView all 14 articles
LDL atherogenicity determined by size, density, oxidation, apolipoprotein(a), and electronegativity: An updated review
Provisionally accepted
Omer Akyol1
Huan-Hsing Chiang1
Alan R Burns2Chao-Yuh Yang3
Darren Woodside4Tatsuya Sawamura5
Jose Luis Sanchez-Quesada6,7Antonio M Gotto8*
Chu-Huang Chen1*- 1Molecular Cardiology Research Laboratories, Vascular and Medicinal Research, The Texas Heart Institute, Houston, Texas, United States
- 2Biological Imaging Core, The University of Houston College of Optometry, Houston, Texas, United States
- 3Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, United States
- 4Molecular Cardiology Research Laboratories, The Texas Heart Institute, Houston, Texas, United States
- 5Department of Molecular Pathophysiology, Shinshu University School of Medicine, Matsumoto, Japan
- 6Cardiovascular Biochemistry, Institut de Recerca Sant Pau (IR-Sant Pau), Barcelona, Spain
- 7CIBER of Diabetes and Metabolic Diseases (CIBERDEM), Barcelona, Spain
- 8Weill Cornell Medical College, New York, NY, United States
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Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease and cerebrovascular disease, is caused by the accumulation of plaque on artery walls. Elevated levels of low-density lipoprotein (LDL) cholesterol significantly contribute to the development and progression of ASCVD. Multiple studies have provided evidence of a correlation between individual LDL subpopulations and the development of atherosclerosis (AS); among these, small, dense low-density lipoprotein (sdLDL) and lipoprotein(a) (Lp(a)) have been particularly implicated. There are multiple considerations of why sdLDL may cause AS including their low affinity for the LDL receptor, their ability to diffuse into the artery wall and remain there for a long time, and their tendency to become excessively oxidized. Oxidized LDL (oxLDL), generated under oxidative stress, drives AS by impairing endothelial function, promoting foam cell formation, and triggering vascular inflammation. Lp(a) contributes to the development and progression of AS by causing inflammation of the arterial wall. Studies conducted in recent years have found that electronegative LDL (L5/LDL(-)) may also be an important factor in the development and progression of AS. L5/LDL(-) causes atherosclerotic changes in the vascular wall by triggering apoptosis in endothelial cells via the lectin-like oxLDL receptor-1. This article offers an updated overview of ASCVD and briefly examines the classifications of atherogenic LDL subfractions and their roles in atherogenesis.
Keywords: Atherosclerosis, Atherosclerotic cardiovascular disease (ASCVD), small, dense LDL (sdLDL), oxidized LDL(oxLDL), lipoprotein(a) (Lp(a)), electronegative LDL (L5/LDL(-))
Received: 19 Jun 2025; Accepted: 30 Sep 2025.
Copyright: © 2025 Akyol, Chiang, Burns, Yang, Woodside, Sawamura, Sanchez-Quesada, Gotto and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Antonio M Gotto, amg2004@med.cornell.edu
Chu-Huang Chen, cchen@texasheart.org
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.