Remnant Lipoprotein Particles Induce Apoptosis in Endothelial Cells by NAD(P)H Oxidase–Mediated Production of Superoxide and Cytokines via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Activation: Prevention by Cilostazol
Abstract
Background— Remnant lipoprotein particles (RLPs), products of lipolytic degradation of triglyceride-rich lipoprotein derived from VLDL, exert atherogenesis. In this study, we observed how RLPs induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and cilostazol prevented cell death. Methods and Results— RLPs were isolated from the plasma of hyperlipidemic patients by use of an immunoaffinity gel mixture of anti–apolipoprotein A-1 and anti–apolipoprotein B-100 monoclonal antibodies. RLPs (50 μg/mL) significantly increased superoxide formation in HUVECs associated with elevated gp91phox mRNA and protein expression and Rac1 translocation, accompanied by increased production of tumor necrosis factor (TNF)-α and interleukin-1β, DNA fragmentation, and cell death. Cilostazol (1 to 100 μmol/L) significantly suppressed not only NAD(P)H oxidase–dependent superoxide production but also TNF-α and interleukin-1β release and restored viability. RLPs activated a lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which was not inhibited by cilostazol. Treatment of HUVECs with monoclonal antibody for LOX-1 attenuated RLP-mediated production of superoxide, TNF-α, and interleukin-1β and DNA fragmentation. Conclusions— RLPs stimulated NAD(P)H oxidase–dependent superoxide formation and induction of cytokines in HUVECs via activation of LOX-1, consequently leading to reduction in cell viability with DNA fragmentation, and cilostazol exerts a cell-protective effect by suppressing these variables.
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The effect of NOX1 in atherosclerosis is contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet and diabetic mouse models, whereas in other cases NOX1 deletion did not seem to have an effect.
“The results of different studies are contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet (854) and diabetic mouse models (380), whereas in other cases, NOX1 deletion did not seem to have an effect (875).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [854]
The role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models.
“Altogether, the role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models (345, 380, 630, 854).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [854]
Postprandial TRL increases the expression of proinflammatory genes, induces apoptosis, and accentuates the inflammatory response of cultured endothelial cells to TNF-α.
“Postprandial TRL (ppTG) has also been shown to increase the expression of proinflammatory genes (eg, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1), 65 induce apoptosis, 66 and accentuate the inflammatory response of cultured endothelial cells to tumor necrosis factor-␣.67”
From Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association (2011) · cites this paper as [66]
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- Authors
- Shin, H. K., Kim, Y. K., Kim, K. Y., Lee, J. H., & Hong, K. W.
- Affiliations
- Pusan National University (KR)
- Venue
- Circulation
- Published
- 2004-03-02
- Volume
- 109
- Issue
- 8
- Pages
- 1022-1028
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2160256386
- Cited by
- 268
- References
- 33
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 15 · 2023: 18 · 2022: 14 · 2021: 16 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 9 · 2015: 9 · 2014: 10 · 2013: 13 · 2012: 15
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- endothelial cell apoptosis, NADPH oxidase, superoxide, LOX-1, cilostazol, TNF-α, IL-1β, gp91phox, Rac1, DNA fragmentation, atherogenesis, hyperlipidemia
- MeSH terms
- NADPH Oxidase 2, Cilostazol, Adult, Arteriosclerosis, Cells, Cultured, Chylomicrons, Endothelium, Vascular, Enzyme Induction, Enzyme Inhibitors, Female, Humans, Interleukin-1, Lipoproteins, Lipoproteins, LDL, Male, Membrane Glycoproteins, Middle Aged, NADPH Dehydrogenase, Phosphoproteins, Receptors, LDL, Superoxides, Tetrazoles, Tumor Necrosis Factor-alpha, Signal Transduction, Cytokines, Apoptosis, NADPH Oxidases, Genistein, rac1 GTP-Binding Protein, Membrane Transport Proteins, Endothelial Cells, Chylomicron Remnants
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