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Published on: October 17, 2017
Macrophage Phospholipase D3 promotes atherosclerosis via exacerbating foam cell formation and inducing inflammatory
Teng Li1, Xiaobao Gu1, Xiangyang Yin1
1Department of Vascular Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Insights
Phospholipase D3 (PLD3) promotes atherosclerosis by increasing lipid buildup and inflammation in macrophages. Targeting PLD3 could be a new therapeutic strategy for treating this cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Atherosclerosis is a significant global health burden.
- Phospholipase D3 (PLD3) is found in atherosclerotic plaques, but its function is unknown.
- Understanding PLD3's role is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role and molecular mechanisms of PLD3 in atherosclerosis.
- To determine if PLD3 is a viable therapeutic target.
Main Methods:
- Single-cell RNA sequencing of human atherosclerotic tissues.
- In vitro studies using THP-1 macrophages and ApoE^-/- mice.
- PLD3 knockdown, oxidized LDL stimulation, lipid accumulation assays, and cytokine quantification.
- RNA sequencing to analyze downstream pathways.
Main Results:
- PLD3 is upregulated in atherosclerotic lesions and macrophages, showing diagnostic potential.
- Oxidized LDL increases PLD3 expression in macrophages.
- PLD3 silencing reduces lipid accumulation via CD36 downregulation and decreases inflammatory cytokines (IL-1β, TNF-α).
- PLD3 deficiency inhibits the NF-κB pathway.
Conclusions:
- PLD3 promotes atherosclerosis by enhancing CD36-mediated lipid uptake and NF-κB-driven inflammation.
- PLD3 is a potential therapeutic target for atherosclerotic disease.
Background:
Atherosclerosis is a chronic inflammatory disease and a major cause of global morbidity and mortality. Phospholipase D3 (PLD3) has been reported to be elevated in atherosclerotic plaques, yet its functional role and molecular mechanisms remain unclear. This study investigated the role of PLD3 in atherosclerosis.
Methods:
Single-cell RNA sequencing of human atherosclerotic tissues was analyzed to define PLD3 expression. Validation was performed in ApoE^-/- mice and THP-1-derived foam cells by qRT-PCR and western blotting. Lentiviral-mediated PLD3 knockdown was followed by oxidized LDL (ox-LDL) stimulation. Lipid accumulation and uptake were assessed by Oil Red O, BODIPY, and DiI-ox-LDL assays, while inflammatory cytokines were quantified by qRT-PCR. RNA sequencing was conducted to explore downstream mechanisms.
Results:
PLD3 expression was markedly upregulated in atherosclerotic lesions and enriched in plaque macrophages, with diagnostic value confirmed by ROC analysis. In vitro, ox-LDL induced PLD3 upregulation in THP-1 macrophages. PLD3 silencing reduced lipid accumulation and uptake through downregulation of CD36, while concurrently decreasing IL-1β and TNF-α expression. Mechanistically, PLD3 deficiency suppressed NF-κB pathway activation.
Conclusion:
PLD3 is highly expressed in plaque macrophages and promotes atherosclerosis by enhancing CD36-mediated lipid accumulation and activating NF-κB-driven inflammation. These findings identify PLD3 as a potential therapeutic target for atherosclerotic disease.
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