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Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein
Published on: October 12, 2017
Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1
Jianxiang Wu1, Zhiqing He, Xiang Gao
11 Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University , Shanghai, People's Republic of China .
Insights
Oxidized high-density lipoprotein (ox-HDL) impairs endothelial progenitor cells (EPCs) function by activating the CD36-p38 MAPK-TSP-1 pathway. This dysfunction contributes to cardiovascular disease and disturbed neovascularization.
Area of Science:
- Cardiovascular Biology
- Cellular Mechanisms
- Oxidative Stress
Background:
- High-density lipoprotein (HDL) protects against cardiovascular events.
- Oxidative modification of HDL (ox-HDL) can lead to pro-atherosclerotic effects.
- Endothelial progenitor cells (EPCs) are crucial for vascular repair but are susceptible to oxidative damage.
Purpose of the Study:
- To investigate the mechanisms by which ox-HDL impairs EPC function.
- To determine the role of specific signaling pathways in ox-HDL-induced EPC dysfunction.
- To explore the clinical relevance of ox-HDL in patients with cardiovascular disease.
Main Methods:
- In vitro studies exposing EPCs to ox-HDL.
- Assessment of EPC apoptosis, proliferation, migration, and cholesterol efflux.
- Analysis of signaling pathway activation (p38 MAPK, NF-κB) and gene expression (TSP-1, VEGF).
- In vivo studies and analysis of patient samples (coronary artery disease, type 2 diabetes).
Main Results:
- Ox-HDL dose-dependently increased EPC apoptosis and reactive oxygen species.
- Ox-HDL reduced EPC migration, angiogenesis, and cholesterol efflux.
- Activation of CD36-p38 MAPK-TSP-1 pathways was observed following ox-HDL stimulation.
- Inverse correlation found between ox-HDL levels and circulating EPC numbers in patients.
Conclusions:
- The CD36-p38 MAPK-TSP-1 pathway activation mediates ox-HDL-induced EPC dysfunction.
- This dysfunction may contribute to impaired neovascularization in chronic ischemic diseases.
- Ox-HDL represents a potential therapeutic target for cardiovascular conditions.
Aims:
High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms.
Results:
ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal.
Innovation:
This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum.
Conclusion:
Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.
