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Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262
J Mezquita1, B Mezquita, M Pau
1Laboratori de Genètica Molecular, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Abstract:
The mechanisms involved in the anti-angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt-1 (vascular endothelial growth factor receptor 1) was down-regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt-1 by lipopolysaccharide (LPS) in macrophages and down-regulated the expression of Flt-1 after LPS induction. Flt-1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt-1, coding for a soluble form of the receptor (sFlt-1) with anti-angiogenic properties, was not down-regulated in the same extent. Only a small decrease in the expression of VEGF and Ang-2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang-1. Since recent experiments have demonstrated the importance of anti-Flt-1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831-840), our observation on down-regulation of Flt-1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.
Insights
Proteasome inhibitors like MG262 reduce vascular endothelial growth factor receptor 1 (Flt-1) gene expression in endothelial cells and macrophages. This finding supports their potential therapeutic use in modulating angiogenesis and inflammation.
Area of Science:
- Molecular Biology
- Cell Biology
- Angiogenesis Research
Background:
- The anti-angiogenic mechanisms of proteasome inhibitors are not fully understood.
- Vascular Endothelial Growth Factor Receptor 1 (Flt-1) plays a crucial role in angiogenesis.
Purpose of the Study:
- To investigate the effect of proteasome inhibitor MG262 on Flt-1 gene expression.
- To explore the potential of proteasome inhibitors in therapeutic angiogenesis and inflammation modulation.
Main Methods:
- Using explant cultures of chicken pecten oculi and human microvascular endothelial cells.
- Employing the reversible proteasome inhibitor MG262.
- Analyzing gene expression of Flt-1, VEGF, Ang-1, Ang-2, and KDR.
Main Results:
- MG262 down-regulated Flt-1 gene expression in chicken pecten oculi and human microvascular endothelial cells.
- MG262 inhibited Flt-1 induction by lipopolysaccharide (LPS) in macrophages.
- Soluble Flt-1 (sFlt-1) transcript levels were less affected; minor decreases in VEGF and Ang-2 were observed.
Conclusions:
- Proteasome inhibitor MG262 down-regulates Flt-1 expression in key vascular and immune cells.
- These findings support the therapeutic potential of proteasome inhibitors for conditions involving angiogenesis and inflammation, such as tumor growth and atherosclerosis.