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.
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|Titolo:||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.|
|Autori:||E., Toschi; G., Barillari; C., Sgadari; I., Bacigalupo; Cereseto, Anna; D., Carlei; C., Palladino; C., Zietz; P., Leone; M., Stürzl; S., Buttò; A., Cafaro; P., Monini; B., Ensoli|
|Titolo del periodico:||MOLECULAR BIOLOGY OF THE CELL|
|Anno di pubblicazione:||2001|
|Codice identificativo Scopus:||2-s2.0-0035158524|
|Codice identificativo Pubmed:||11598182|
|Codice identificativo WOS:||WOS:000171540300003|
|Appare nelle tipologie:||03.1 Articolo su rivista (Journal article)|