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HIV-1 Tat increases endothelial solute permeability through tyrosine kinase and mitogen-activated protein kinase-dependent pathways

Oshima, Tadayuki; Flores, Sonia C.a; Vaitaitis, Giselaa; Coe, Laura L.; Joh, Takashib; Park, Jae H.; Zhu, Yanan; Alexander, Brett; Alexander, J. Steven

Basic Science

Objective: HIV-1 infection is associated with alterations of several vascular endothelial functions including adhesion molecule expression, growth, and vascular permeability. The bases of these errors are not known, but might involve secretion of the HIV-1 derived transcription factor `Tat-1'. This study investigated Tat-1 mediated endothelial barrier changes and second message regulation of this phenomenon.

Methods: We exposed human umbilical vein endothelial cell monolayers to Tat-1 (0–150 ng/ml) for up to 48 h and measured resulting changes in monolayer permeability. We also investigated the role of tyrosine and mitogen activated protein (MAP) kinases, and protein kinase G using the pharmacological blockers genistein, PD98059 and KT5823 respectively.

Results: Tat-1 significantly reduced monolayer barrier and increased albumin permeability within 24 h. Tat-1 also stimulated tyrosine phosphorylation of multiple endothelial proteins, disorganized junctional phosphotyrosine staining and increased the number of these immunostaining structures. The increased permeability produced by Tat-1 was blocked by genistein and PD98059, but not by KT5823. Genistein and PD98059 pretreatment also prevented the changes in phosphotyrosine immunostaining produced by Tat-1 and blocked phosphorylation of several proteins including MAP kinase.

Conclusion: These results suggest that HIV may dysregulate endothelial barrier through the effects of Tat-1. These blocker experiments suggest that the effects of Tat are transcription/translation-dependent. These data demonstrate that Tat increases endothelial albumin permeability in vitro through tyrosine kinase and MAP kinase, but not protein kinase G pathways.

From the Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, aWebb-Waring Institute for Biomedical Research, Denver, Colorado, USA, bFirst Department of Internal Medicine, Nagoya City University Medical School, Japan.

Sponsorship: Supported by NIH grants DK43785, HL47615, and HL59785.

Requests for reprints to: J.S. Alexander. Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, 1501 Kings Highway, Shreveport, Louisiana, 71130-3932, USA.

Received: 24 August 1999;

revised: 25 November 1999; accepted: 8 December 1999.

© 2000 Lippincott Williams & Wilkins, Inc.