description) The HIV-1 TAT protein is secreted from infected T-cells and monocyte-macrophages, and prior studies suggest it can potently alter endothelial growth, migration and adhesive interactions. The functional effects of TAT on endothelium appear to occur via its specific binding to the Flk-1/KDR receptor for vascular endothelial growth factor (VEGF) and to the alpha5 beta1, alphav beta3 and alphav beta5 surface integrins. This group recently have found that TAT can activate the FLT4 receptor for VEGF-C/VRP, as well as several Src kinase family members, the protein tyrosing phosphatase SHPTP-2, the focal adhesion kinases FAK and RAFTK/Pyk2 and the p44/42 MAP kinases Erk1 and 2. Moreover, TAT treatment of human umbilical vein endothelium cells (HUVEC) or bone marrow endothelium cells (BMEC) resulted in the release of nitric oxide (NO), increased protein levels of endothelial nitric oxide synthase (eNOS), and generation of the beta-chemokine monocyte chemotactic protein (MCP-1). NO is an important mediator of VEGF effects on vascular cell growth, chemotaxis and permeability. MCP-1 contributes to recruitment of monocyte-macrophages and T-cells and is believed to mediate transmigration of T-cells across an endothelial monolayer. The observations on TAT, coupled with previously reported work, suggest that it can subvert several vital endothelial functions by co-opting surface VEGF and integrin receptor triggered signal transduction pathways. This proposal seeks to systematically characterize the signaling pathways utilized by TAT in HUVEC and BMEC, and contrast them with those triggered by VEGF-A and VEGF-C/VRP, in order to determine the mechanisms of TAT-mediated mitogenesis, chemotaxis, adhesion molecule expression, and NO and MCP-1 release. The information obtained from these studies should help in defining how HIV-1 may cause endothelial dysfunction and injury, and assist in the creation of novel therapeutics to protect the HIV infected host.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061940-03
Application #
6184571
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Wang, Lan-Hsiang
Project Start
1998-09-20
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$304,500
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, Xuefeng; Wang, Jian Feng; Kunos, George et al. (2007) Cannabinoid modulation of Kaposi's sarcoma-associated herpesvirus infection and transformation. Cancer Res 67:7230-7
Zhang, Xuefeng; Groopman, Jerome E; Wang, Jian Feng (2005) Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1. J Cell Physiol 202:205-14
Wang, Jian Feng; Zhang, Xuefeng; Groopman, Jerome E (2004) Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. J Biol Chem 279:27088-97
Choe, Evangeline Y; Schoenberger, Elena S; Groopman, Jerome E et al. (2002) HIV Nef inhibits T cell migration. J Biol Chem 277:46079-84
Park, I W; Wang, J F; Groopman, J E (2001) HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes. Blood 97:352-8
Wang, J F; Zhang, X F; Groopman, J E (2001) Stimulation of beta 1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. J Biol Chem 276:41950-7
Park, I W; Ullrich, C K; Schoenberger, E et al. (2001) HIV-1 Tat induces microvascular endothelial apoptosis through caspase activation. J Immunol 167:2766-71
Ganju, R K; Brubaker, S A; Chernock, R D et al. (2000) Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk. J Biol Chem 275:17263-8