Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells.
OBJECTIVE
It has been proposed that human immunodeficiency virus (HIV) infection-induced inflammatory environment may contribute to the pathogenesis of cardiovascular diseases. Recent studies have also demonstrated the potential role of estrogen as therapeutic agents in the prevention or treatment of cardiovascular diseases. In the present study, we assessed the hypothesis that estrogen may attenuate the HIV Tat protein-induced inflammatory pathways in human vascular endothelium.


METHODS
Expression of inflammatory mediators in human endothelial cells was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Electrophoretic mobility shift assay (EMSA) also was performed to investigate the DNA-binding activities of several transcription factors, which are known to regulate expression of these inflammatory genes.


RESULTS
Acute exposure of human endothelial cells to Tat markedly induced the mRNA and protein expression of IL-1beta, MCP-1, VCAM-1, and E-selectin. Tat also stimulated the adherence of inflammatory cells to endothelial cell monolayers. Significant and dose-dependent increases in NF-kappaB DNA-binding activity were observed in human endothelial cells treated with Tat. However, Tat did not affect DNA-binding activities of AP-1, CREB, and STAT1. Pretreatment with 17beta-estradiol dramatically blocked the activation of NF-kappaB in human endothelial cells exposed to Tat. In addition, 17beta-estradiol selectively inhibited the Tat-induced expression of IL-1beta.


CONCLUSIONS
Our results suggest that estrogen may protect against Tat-induced inflammatory reactions in human vascular endothelium via blocking the NF-kappaB-mediated molecular signaling pathways. These data may contribute to understanding the pathogenesis of cardiovascular complications and development of therapeutic strategies for HIV-infected patients.
Lee
Yong Woo
YW
Department of Surgery/Division of Neurosurgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA. ylee2@uky.edu
Eum
Sung Yong
SY
Nath
Avindra
A
Toborek
Michal
M
D002448:Cell Adhesion / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics; D016207:Cytokines / Q000032:analysis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019040:E-Selectin / Q000032:analysis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004958:Estradiol / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D018932:Chemokine CCL2; D016207:Cytokines; D019040:E-Selectin; D015696:Gene Products, tat; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D054322:tat Gene Products, Human Immunodeficiency Virus; D004958:Estradiol; D004247:DNA