Infection of patients with Human Immunodeficiency Virus 1 (HIV) is associated with diverse alterations in endothelial function. These include syndromes marked by inappropriate endothelial cell (EC hyperplasia (primary pulmonary hypertension), incomplete differentiation (Kaposi's sarcoma), and acute inflammation (pneumonitis, myocarditis, encephalitis, pericarditis). Although these perturbations in EC function can be diffuse, direct infection of EC by HIV is unusual, may be restricted to certain vascular beds, and is generally abortive. Such endothelial alterations are therefore more likely to be the result of HIV-related circulating mediators, rather than of direct endothelial infection by retrovirus. We hypothesize that the secreted HIV transcription factor Tat acts to modify EC proliferation, differentiation, apoptosis, and expression of inflammatory molecules, and additionally, that these effects are modulated by the cytokines TNF alpha, IL-1 beta, and IFN gamma. We further hypothesize that the diverse and sometimes opposing effects of Tat are mediated by the oxidant-dependent differential activation of the various MAP Kinase signaling cassettes. Our preliminary data confirm that exposure of human EC to Tat acutely increases intracellular oxidant levels concomitant with activation of c-Jun amino terminal kinase (JNK). Further, Tat alters the TNF-alpha- mediated activation of JNK and the DNA-binding affinity of the transcription factor AP-1, a potential target of JNK. Our general objectives are to correlate oxidase assembly, oxidant production, MAPK activation, and DNA binding and promoter activation of transcription factors, with cell phenotype (proliferation, differentiation, apoptosis, inflammatory molecule expression, and leukocyte adhesion) in human EC exposed to Tat and cytokines, using a variety of interventions designed to dissect different signaling pathways. The significance of this work is to provide further insight into the cause of various AIDS-related vascular syndromes, as well as to understand the basis for fundamental EC functions in normal individuals. This may lead to specific treatments for HIV-infected patients, and may also suggest novel strategies for treatment of non-HIV related diseases through modulation of endothelial cell function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL061897-02
Application #
2908628
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Project Start
1998-09-30
Project End
2003-07-31
Budget Start
1999-01-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Li, Xichuan; Xu, Zhao; Du, Wei et al. (2014) Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer Cell 25:575-89
Wu, Ru-Feng; Ma, Zhenyi; Liu, Zhe et al. (2010) Nox4-derived H2O2 mediates endoplasmic reticulum signaling through local Ras activation. Mol Cell Biol 30:3553-68
Ma, Z; Liu, Z; Wu, R-F et al. (2010) p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior. Oncogene 29:5559-67
Liu, Zhe; Ma, Zhenyi; Terada, Lance S et al. (2009) Divergent roles of RelA and c-Rel in establishing chromosomal loops upon activation of the Igkappa gene. J Immunol 183:3819-30
Wu, Ru Feng; Terada, Lance S (2009) Ras and Nox: Linked signaling networks? Free Radic Biol Med 47:1276-81
Hormi-Carver, Kathy; Zhang, Xi; Zhang, Hui Ying et al. (2009) Unlike esophageal squamous cells, Barrett's epithelial cells resist apoptosis by activating the nuclear factor-kappaB pathway. Cancer Res 69:672-7
Dumka, Disha; Puri, Poonam; Carayol, Nathalie et al. (2009) Activation of the p38 Map kinase pathway is essential for the antileukemic effects of dasatinib. Leuk Lymphoma 50:2017-29
Feagins, Linda A; Zhang, Hui Ying; Zhang, Xi et al. (2008) Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines. Am J Physiol Gastrointest Liver Physiol 294:G411-7
Terada, Lance S (2008) What underlies endothelial shear sensing? The matrix, of course. Circ Res 103:562-4
Ma, Zhenyi; Liu, Zhe; Myers, David P et al. (2008) Mechanotransduction and anoikis: death and the homeless cell. Cell Cycle 7:2462-5

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