Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262.

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.

• Authors: J Mezquita, B Mezquita, M Pau, C Mezquita
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 89 Issue 6 Pg. 1138-47 (Aug 15 2003) ISSN: 0730-2312 [Print] United States
• PMID: 12898512 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• 3' Untranslated Regions
• Boronic Acids
• DNA Primers
• Enzyme Inhibitors
• Lipopolysaccharides
• MG 262
• Multienzyme Complexes
• Vascular Endothelial Growth Factor Receptor-1
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Base Sequence
• Blotting, Northern
• Boronic Acids (pharmacology)
• Cells, Cultured
• Chick Embryo
• Cysteine Endopeptidases
• DNA Primers
• Down-Regulation
• Endothelial Cells (drug effects, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Humans
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Molecular Sequence Data
• Multienzyme Complexes (antagonists & inhibitors)
• Organ Culture Techniques
• Proteasome Endopeptidase Complex
• Retinal Vessels (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Homology, Nucleic Acid
• Vascular Endothelial Growth Factor Receptor-1 (drug effects, genetics)