Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells
| Autor: | Bei Zhang, Lei Chen, Bernhard Hennig, Wen Huang, Geun Bae Rha, Ibolya E. András, Dennis Bruemmer, Michal Toborek, Melissa J. Seelbach |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Telomerase
Physiology Cell HIV Infections Biology Cell junction Cell Line Tight Junctions Mice Downregulation and upregulation Cell Movement Physiology (medical) medicine Animals Humans Telomerase reverse transcriptase Claudin-5 Gene Silencing Cells Cultured Mice Knockout Tight junction NF-kappa B Membrane Proteins U937 Cells Articles Intercellular Adhesion Molecule-1 Telomere Cell biology Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Matrix Metalloproteinase 9 Cell culture Immunology HIV-1 Female tat Gene Products Human Immunodeficiency Virus Endothelium Vascular Cardiology and Cardiovascular Medicine |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 298:H1136-H1145 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.01126.2009 |
| Popis: | 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-κB-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|