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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells.

Authors: Huang, Wen; Rha, Geun Bae; Chen, Lei; Seelbach, Melissa J; Zhang, Bei; András, Ibolya E; Bruemmer, Dennis; Hennig, Bernhard; Toborek, Michal

Published In Am J Physiol Heart Circ Physiol, (2010 Apr)

Abstract: Telomerase, via its catalytic component telomerase reverse transcriptase (TERT), extends telomeres of eukaryotic chromosomes. The importance of this reaction is related to the fact that telomere shortening is a rate-limiting mechanism for human life span that induces cell senescence and contributes to the development of age-related pathologies. The aim of the present study was to evaluate whether the modulation of telomerase activity can influence human immunodeficiency virus type 1 (HIV-1)-mediated dysfunction of human brain endothelial cells (hCMEC/D3 cells) and transendothelial migration of HIV-1-infected cells. Telomerase activity was modulated in hCMEC/D3 cells via small interfering RNA-targeting human TERT (hTERT) or by using a specific pharmacological inhibitor of telomerase, TAG-6. The inhibition of hTERT resulted in the upregulation of HIV-1-induced overexpression of intercellular adhesion molecule-1 via the nuclear factor-kappaB-regulated mechanism and induced the transendothelial migration of HIV-1-infected monocytic U937 cells. In addition, the blocking of hTERT activity potentiated a HIV-induced downregulation of the expression of tight junction proteins. These results were confirmed in TERT-deficient mice injected with HIV-1-specific protein Tat into the cerebral vasculature. Further studies revealed that the upregulation of matrix metalloproteinase-9 is the underlying mechanisms of disruption of tight junction proteins in hCMEC/D3 cells with inhibited TERT and exposed to HIV-1. These results indicate that the senescence of brain endothelial cells may predispose to the HIV-induced upregulation of inflammatory mediators and the disruption of the barrier function at the level of the brain endothelium.

PubMed ID: 20139322 Exiting the NIEHS site

MeSH Terms: Animals; Cell Line; Cell Movement/physiology*; Cells, Cultured; Claudin-5; Disease Models, Animal; Endothelium, Vascular/drug effects; Endothelium, Vascular/pathology; Endothelium, Vascular/virology*; Female; Gene Silencing; HIV Infections/metabolism; HIV Infections/pathology; HIV-1/isolation & purification*; Humans; Intercellular Adhesion Molecule-1/metabolism; Matrix Metalloproteinase 9/metabolism; Membrane Proteins/metabolism*; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B/metabolism; Telomerase/antagonists & inhibitors*; Telomerase/genetics; Telomerase/metabolism; Tight Junctions/metabolism*; U937 Cells; tat Gene Products, Human Immunodeficiency Virus/pharmacology

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