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1α, 25-dihydroxyvitamin D3 attenuates tumor necrosis factor-α-induced endothelial cell injury by modulating the tumor
Yangyang Xia1, Sixiu Liu1, Qiuyuan Shao1
1Department of Nephrology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Insights
The active form of vitamin D, 1α,25-dihydroxyvitamin D3, reduces inflammatory adhesion molecules in endothelial cells. This occurs by inhibiting the tumor necrosis factor-α (TNF-α)/nuclear factor kappa-B (NF-κB) pathway, suggesting potential cardiovascular disease treatments.
Area of Science:
- Endocrinology
- Molecular Biology
- Cardiovascular Research
Background:
- Cardiovascular diseases are a leading cause of death, with endothelial dysfunction as a common pathology.
- Low vitamin D levels are linked to endothelial dysfunction, but mechanisms are unclear.
- Targeting endothelial cell function is crucial for treating cardiovascular diseases.
Purpose of the Study:
- To investigate the effects of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on adhesion molecule expression in human endothelial cells.
- To explore the underlying molecular mechanisms involving the NF-κB signaling pathway.
Main Methods:
- Human umbilical vein endothelial cells were treated with 1α,25(OH)2D3 and TNF-α.
- Western blotting and RT-PCR assessed VCAM-1 and E-selectin expression.
- ChIP assays, immunofluorescence, and coimmunoprecipitation analyzed NF-κB pathway activation.
Main Results:
- 1α,25(OH)2D3 significantly inhibited TNF-α-induced VCAM-1 and E-selectin mRNA and protein expression.
- 1α,25(OH)2D3 suppressed TNF-α-induced NF-κB activation and p65 binding to target gene promoters.
- Vitamin D receptor (VDR) interaction with p65 was enhanced by 1α,25(OH)2D3, blocking NF-κB translocation.
Conclusions:
- 1α,25(OH)2D3 regulates endothelial adhesion molecule expression via the TNF-α/NF-κB pathway.
- This study provides a mechanistic basis for using 1α,25(OH)2D3 in treating cardiovascular diseases.
- Targeting the VDR-NF-κB interaction offers a novel therapeutic strategy for endothelial dysfunction.
Objective:
Cardiovascular (CV) diseases remain the leading cause of death in modern societies, with endothelial dysfunction being the common pathology of CV diseases with various etiologies. Therefore, effectively regulating the function of endothelial cells is considered the key to the future treatment of various CV diseases. Low levels of vitamin D and its analogs have been shown to be associated with endothelial dysfunction in various diseases. However, the underlying mechanism remains unknown. Here, we conducted an in vitro study to evaluate the effects of 1α,25-dihydroxyvitamin D3 (1α, 25(OH)2D3), the active form of vitamin D, on adhesion molecule expression in human endothelial cells. The possible mechanism involved in this process was also explored.
Material And Methods:
Human umbilical vein endothelial cells were cultured and treated according to the experimental requirements. Western blotting and reverse transcription polymerase chain reaction were used to evaluate the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Chromatin immunoprecipitation (ChIP) assays, immunofluorescence, Western blotting, and coimmunoprecipitation were used to assess the effects of 1α, 25(OH)2D3 on nuclear factor kappa-B (NF-κB) signaling.
Results:
1α, 25(OH)2D3 inhibited VCAM-1 and E-selectin mRNA and protein expression after tumor necrosis factor-α (TNF-α) stimulation. Moreover, 1α, 25(OH)2D3 affected TNF-α-induced IκBα phosphorylation and p65 NF-κB activation, leading to the inhibition of p65 expression. A ChIP assay revealed that TNF-α increased p65 binding to the promoters of VCAM-1 and E-selectin, which was suppressed by 1α, 25(OH)2D3. These effects were abrogated by a specific vitamin D receptor siRNA (VDR-siRNA). Coimmunoprecipitation revealed that 1α, 25(OH)2D3 induced increased binding of the vitamin D receptor to p65, which inhibited the ability of p65 to bind to target gene promoters.
Conclusion:
1α, 25(OH)2D3 regulates adhesion molecule expression in endothelial cells through the TNF-α/NF-κB pathway, laying the foundation for the clinical application of 1α, 25(OH)2D3 in the treatment of CV diseases.
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