4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 22-25 September 2002, San Diego, CA, USA

HIGHLY ACTIVE ANTIRETROVIRAL DRUGS MODULATE HUMAN AORTIC ENDOTHELIAL CELL FUNCTION: ROLE OF CELL ADHESION MOLECULES, NITRIC OXIDE AND REACTIVE OXYGEN SPECIES

Antiviral Therapy 2002; 7:L8 (abstract 12)

KC Agrawal, L Pradhan, M Ali and D Mondal
Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, La., USA

The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis in HIV-1 infected patients. However, long term HAART is associated with lipodystrophy and cardiovascular complications leading to a progressive deterioration in the patient’s quality of life. The HIV-1 protease inhibitors (PIs) are often included in the HAART regimen in combination with a nucleoside and a nonnucleoside reverse transcriptase inhibitor. We have previously shown that PIs can induce insulin resistance in adipocytes. Since insulin also plays an important role in maintaining endothelium dependent vascular homeostasis, we investigated the effects of HAART exposure to human aortic endothelial cells (HAECs). The HAART regimen included zidovudine (1-3 µM), efavirenz (3-9 µM) and nelfinavir or indinavir (3-9 µM). The effects of HAART exposure on HAECs were investigated by monitoring the following parameters: (1) leukocyte adhesion, (2) gene expression of cell adhesion molecules (CAMs) and nitric oxide (NO)-synthase (eNOS), (3) NO production, and (4) generation of reactive oxygen species (ROS). Treatment of HAECs with either the PIs alone or HAART regimen (24-72 h) showed a concentration dependent increase (four- to 12-fold) in adhesion of leukocytes (Jurkats) that was significantly inhibited upon cotreatment with insulin (50 mU/ml), N-acetyl cysteine (0.5%) or sodium nitroprusside (25 µM). RT-PCR studies demonstrated an increase (two- to 2.5-fold) in both VCAM and ICAM-1 gene expression whereas eNOS gene expression was significantly decreased (three- to fivefold) as monitored by real time RT-PCR. The insulin (50 mU/ml) induced NO production, determined by Greiss reagent, decreased by 83%. Under these conditions superoxide anion formation, determined by a luminometer, was increased four- to sixfold that peaked at 60 min following PMA stimulation. In conclusion, these findings suggest that exposure of endothelial cells to PI-containing HAART regimens may induce insulin resistance, increase adhesion properties, decrease endothelial NO formation and increase ROS production. These factors may lead to endothelial dysfunction observed in HIV-1-positive individuals.

Supported in part by the NIH grant RO1DK58499.

Presenting author: KC Agrawal

2002-09-22
12

Copyright © 2002 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.