Activation of matrix-metalloproteinase-2 and membrane-type-1-matrix-metalloproteinase in endothelial cells and induction of vascular permeability in vivo by human immunodeficiency virus-1 Tat protein and basic fibroblast growth factor.

Abstract

Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV-uninfected individuals with classic KS, indicating that these mechanisms are operative in AIDS-KS. This suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.

• Authors: E Toschi, G Barillari, C Sgadari, I Bacigalupo, A Cereseto, D Carlei, C Palladino, C Zietz, P Leone, M Stürzl, S Buttò, A Cafaro, P Monini, B Ensoli
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 12 Issue 10 Pg. 2934-46 (Oct 2001) ISSN: 1059-1524 [Print] United States
• PMID: 11598182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gene Products, tat
• Tissue Inhibitor of Metalloproteinases
• tat Gene Products, Human Immunodeficiency Virus
• Fibroblast Growth Factor 2
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Acquired Immunodeficiency Syndrome (enzymology)
• Animals
• Capillary Permeability (physiology)
• Cells, Cultured
• Edema (metabolism)
• Endothelium, Vascular (cytology, enzymology)
• Enzyme Activation (physiology)
• Fibroblast Growth Factor 2 (metabolism)
• Gene Products, tat (metabolism)
• Guinea Pigs
• Humans
• Lung (cytology)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Sarcoma, Kaposi (enzymology)
• Tissue Inhibitor of Metalloproteinases (metabolism)
• tat Gene Products, Human Immunodeficiency Virus