Endothelial Cell Biology and HIV-1 Infection

Tat, the transactivator of HIV-1 gene expression, is released by acutely HIV-1-infected T-cells and promotes adhesion, migration, and growth of inflammatory cytokine-activated endothelial and Kaposi's sarcoma cells. It has been previously demonstrated that these effects of Tat are due to its ability to bind through its arginine-glycine-aspartic (RGD) region to the α5β1 and αvβ3 integrins. However, the signaling pathways linking Tat to the regulation of cellular functions are incompletely understood. Here, we report that Tat ligation on human endothelial cells results in the activation of the small GTPases Ras and Rac and the mitogen-activated protein kinase ERK, specifically through its RGD region. In addition, we demonstrated that Tat activation of Ras, but not of Rac, induces ERK phosphorylation. We also found that the receptor proximal events accompanying Tat-induced Ras activation are mediated by tyrosine phosphorylation of Shc and recruitment of Grb2. Moreover, Tat enabled endothelial cells to progress through the G1 phase in response to bFGF, and the process is linked to ERK activation. Taken together, these data provide novel evidence about the ability of Tat to activate the Ras-ERK cascade which may be relevant for endothelial cell proliferation and for Kaposi's sarcoma progression.

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Identification of endothelial cell genes by combined database mining and microarray analysis

Physiological Genomics ◽

10.1152/physiolgenomics.00186.2002 ◽

2003 ◽

Vol 13 (3) ◽

pp. 249-262 ◽

Cited By ~ 80

Author(s):

Michael Ho ◽

Eugene Yang ◽

George Matcuk ◽

David Deng ◽

Nick Sampas ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Biology ◽

Soft Tissues ◽

Expression Profiles ◽

Differentially Expressed ◽

Primary Data ◽

Database Mining ◽

Novel Genes

Vascular endothelial cells maintain the interface between the systemic circulation and soft tissues and mediate critical processes such as inflammation in a vascular bed-selective fashion. To expand our understanding of the genetic pathways that underlie these specific functions, we have focused on the identification of novel genes that are differentially expressed in all endothelial cells, as well as restricted groups of this cell type. Virtual subtraction was conducted employing gene expression data deposited in public databases and 384 genes identified.11 The microarray data derived through these experiments have been deposited in the GEO expression database at the NCBI and has been given the accession number GPL217 , with others pending. Primary data and supplementary material associated with this manuscript are being deposited at the following website: http://quertermous.stanford.edu . These genes were spotted on custom microarrays, along with 288 genes identified through subtraction cloning from TGF-β-stimulated endothelial cells. Arrays were evaluated with RNA samples representing endothelial cells cultured from four vascular sources and five non-endothelial cell types. These studies identified 64 pan-endothelial markers that were differentially expressed with at least a threefold difference (range 3- to 55-fold). In addition, differences in gene expression profiles among endothelial cells from different vascular beds were identified. Validation of these findings was performed by RNA blot expression studies, and a number of the novel genes were shown to be expressed under angiogenic conditions in the developing mouse embryo. The combined tools of database mining and transcriptional profiling thus provide expanded knowledge of endothelial cell gene expression and endothelial cell biology.

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Effects of the combination of TRC105 and bevacizumab on endothelial cell biology

Investigational New Drugs ◽

10.1007/s10637-014-0129-y ◽

2014 ◽

Vol 32 (5) ◽

pp. 851-859 ◽

Cited By ~ 28

Author(s):

Yingmiao Liu ◽

Hongyu Tian ◽

Gerard C. Blobe ◽

Charles P. Theuer ◽

Herbert I. Hurwitz ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Biology

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Use of High Throughput Genomic Tools for the Study of Endothelial Cell Biology

Lymphatic Research and Biology ◽

10.1089/153968503321642624 ◽

2003 ◽

Vol 1 (2) ◽

pp. 133-145 ◽

Cited By ~ 6

Author(s):

Raymond Tabibiazar ◽

Thomas Quertermous

Keyword(s):

Endothelial Cell ◽

High Throughput ◽

Cell Biology ◽

Genomic Tools

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Abstract 66: The Role of the Viral Nef Protein as a Mediator of HIV-1--Induced Endothelial Dysfunction

Circulation Research ◽

10.1161/res.111.suppl_1.a66 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Ting Wang

Keyword(s):

Cardiovascular Disease ◽

T Cells ◽

Endothelial Cells ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Binding Site ◽

Cell Activation ◽

Endothelial Activation ◽

Endothelial Cell Activation ◽

Hiv 1

With the prevalence of antiviral therapy in the developed world, many HIV-1-infected people die of diseases other than AIDS. One of the emerging major causes is cardiovascular disease, leading to the prediction that the majority of HIV-1 patients are expected to develop cardiovascular complications. Endothelial dysfunction is thought to be a key event in the development of cardiovascular diseases, particularly atherosclerosis. Assays testing the effect of HIV-1 on endothelial activation shows that direct contact with HIV-1 infected T cells enhance endothelial cell activation to a greater extent than HIV-1 alone, suggesting an intracellular HIV-1 protein is responsible for endothelial activation. The HIV-1 viral protein Nef, which is responsible for T cell activation and maintenance of high viral loads in vivo , has been shown to mediate its own transfer to bystander cells. We demonstrate here for the first time that Nef induces nanotube-like conduits connecting T cells and endothelial cells. We also show that Nef is transferred from T cells to endothelial cells via these nanotubes, and is necessary and sufficient for endothelial cell activation. Moreover, we show that SIV-infected macaques exhibit endothelial Nef expression in coronary arteries. Nef expression in endothelial cells causes endothelial apoptosis, ROS and MCP-1 production. Interestingly, a Nef SH3 binding site mutant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through an NADPH oxidase- and ROS-dependent mechanism, while Nef-induced MCP-1 production is NF-kB dependent. Taken together, these data suggest that Nef can mediate its transfer from T cells to endothelial cells through nanotubes to enhance endothelial dysfunction.Thus, Nef is a promising new therapeutic target for reducing the risk for cardiovascular disease in the HIV-1 positive population.

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