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.
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.
Toschi
E
E
Laboratory of Virology, Istituto Superiore di Sanità, 00161 Rome, Italy.
Barillari
G
G
Sgadari
C
C
Bacigalupo
I
I
Cereseto
A
A
Carlei
D
D
Palladino
C
C
Zietz
C
C
Leone
P
P
Stürzl
M
M
Buttò
S
S
Cafaro
A
A
Monini
P
P
Ensoli
B
B
D000163:Acquired Immunodeficiency Syndrome / Q000201:enzymology; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D004487:Edema / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015696:Gene Products, tat / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012514:Sarcoma, Kaposi / Q000201:enzymology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D019714:Tissue Inhibitor of Metalloproteinases; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9