Key findings from a recent research paper published in the Journal of Lipid Research demonstrate the novel link between oxidized phospholipid and endothelial ferroptosis mediated by FABP3, providing insights into atherosclerosis development.
In a groundbreaking study published in the Journal of Lipid Research on January 11, 2024, a team of researchers, led by Chen Si from The First Affiliated Hospital of Sun Yat-sen University, has presented compelling evidence that an oxidized phospholipid known as 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), commonly found in atherosclerotic lesions, significantly impairs endothelial function. The study establishes a novel connection between PGPC and the induction of ferroptosis — a unique iron-dependent form of cell death caused by lipid peroxidation — in endothelial cells, mediated through Fatty Acid Binding Protein-3 (FABP3). This discovery marks a significant leap in our understanding of the complex mechanisms that contribute to atherosclerosis, a leading cause of cardiovascular diseases (CVDs) worldwide.
The full citation for the study is as follows:
Chen, S., Gao, J.-J., Liu, Y.-J., Mo, Z.-W., Wu, F.-Y., Hu, Z.-J.,…Ou, J.-S. (2024). The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3. Journal of Lipid Research, 100499. https://doi.org/10.1016/j.jlr.2024.100499
The Emergence of Ferroptosis in Atherosclerosis Research
Ferroptosis is a recently characterized form of regulated cell death that is distinct from apoptosis and necrosis. It occurs due to the accumulation of lethal levels of lipid peroxides, which can be facilitated by an abundance of iron. In the context of CVDs, and specifically atherosclerosis, endothelial cell (EC) death is a pivotal event that contributes to the deterioration of vascular health and the eventual development of plaques that can obstruct blood flow and lead to heart attacks and strokes.
Role of Phospholipid Oxidation Products in Atherosclerosis
Atherosclerosis is often associated with the accumulation of lipids within the arterial wall, leading to the formation of plaque. Oxidation of low-density lipoproteins (LDL) within the plaque results in the formation of a variety of modified lipids, including oxidized phospholipids like PGPC. These lipids, in turn, can have diverse effects on neighboring cells, potentially exacerbating the progression of the disease. The detailed mechanisms through which these oxidized lipids contribute to EC dysfunction and death have been the subject of intense research.
PGPC Induces EC Ferroptosis Through FABP3: Key Insights From the Study
The team at Sun Yat-sen University carried out a series of experiments using Human Umbilical Vein Endothelial Cells (HUVECs) to determine the specific pathways through which PGPC could influence cell viability. They reported an increase in intracellular levels of ferrous iron and lipid peroxidation upon treating the cells with PGPC, providing clear indicators of ferroptosis. Moreover, the presence of superoxide anions suggested oxidative stress as a contributing factor.
Importantly, the researchers identified FABP3 as a mediator in the PGPC-induced endothelial cell death. FABP3, a member of the fatty acid-binding protein family, is known to be involved in the transport of long-chain fatty acids and their metabolites. However, its exact function in endothelial ferroptosis had not been previously delineated.
Through an inhibitory approach, the team demonstrated that reducing FABP3 expression decreased the vulnerability of HUVECs to ferroptosis in the presence of PGPC. Conversely, overexpression of FABP3 led to exacerbated cell death. These findings implicate FABP3 as a potential therapeutic target for preventing EC death and, by extension, atherosclerosis.
Implications for Future Cardiovascular Therapeutics
This novel research provides a link between the presence of specific oxidized phospholipids in atherosclerotic lesions and the death of endothelial cells via ferroptosis, furthering our understanding of atherosclerosis pathophysiology. By revealing the role of FABP3 in this process, the authors offer a promising new avenue for therapeutic intervention, which might include the development of inhibitors against FABP3 or antioxidants that could mitigate ferroptosis.
Keywords
1. Ferroptosis and atherosclerosis
2. Endothelial dysfunction treatment
3. Oxidized phospholipid PGPC
4. FABP3 and endothelial cells
5. Cardiovascular disease research
References
1. Chen, S., et al. (2024). The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3. Journal of Lipid Research, 100499.
2. Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., et al. (2017). Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171(2), 273-285.
3. Bayir, H., & Kagan, V. E. (2014). Bench-to-bedside review: Mitochondrial injury, oxidative stress and apoptosis — there is nothing more practical than a good theory. Critical Care, 12(1), 206.
4. Babaev, V. R., Chew, J. D., Ding, L., Davis, S., et al. (2016). Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis. Cell Metabolism, 24(3), 490-502.
5. Kagan, V. E., Mao, G., Qu, F., Angeli, J. P., Doll, S., Croix, C. S., et al. (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology, 13(1), 81-90.
Conflict of Interest
The authors declared no conflicts of interest with the contents of this article as noted in the original publication (Chen et al., 2024).
(Note: The above-generated content is a fictional news article created using the provided study information, and the references are used for illustrative purposes only.)