Cysteine-rich and basic domain HIV-1 Tat peptides inhibit angiogenesis andinduce endothelial cell apoptosis

Previous findings suggest that both the Tat polypeptide encoded by HIV-1 an d Tat-derived peptides can induce angiogenesis via activation of the KDR re ceptor for Vascular Endothelial Growth Factor (VEGF), We identified 20 amin o acids and 12 amino acid peptides corresponding to the cysteine-rich and b asic domains of HIV-1 Tat which inhibited I-125-VEGF(165) binding to KDR an d neuropilin-1 (NP-1) receptors in endothelial cells. Cysteine-rich and bas ic Tat peptides inhibited VEGF-induced ERK activation and mitogenesis in en dothelial cells, and inhibited angiogenesis in vitro at concentrations simi lar to those which inhibited VEGF receptor binding. These peptides also inh ibited proliferation, angiogenesis, and ERK activation induced by basic fib roblast growth factor with similar potency and efficacy. Surprisingly, we f ound that both cysteine-rich and basic domain Tat peptides strikingly induc ed apoptosis in endothelial cells, independent of their effects on VEGF and bFGF. Furthermore, we found no evidence for direct biological effects of r ecombinant Tat on VEGF receptor binding, ERK activation, endothelial cell s urvival, or mitogenesis. These findings demonstrate novel properties of Tat -derived peptides and indicate that their major effect in endothelial cells is apoptosis independent of specific inhibition of VEGF receptor activatio n. (C) 2001 Academic Press.