Pentoxifylline Reduces Endothelial Activation Induced by Cytokine and HIV Derived Peptides: Implications for HIV‐Associated Cardiovascular Disease

Abstract

HIV infection is associated with increased serum levels of inflammatory markers, endothelial dysfunction, and cardiovascular events. Here we investigated the hypothesis that HIV infection enhances the activity of proinflammatory cytokines on endothelial cell activation, and assessed anti‐inflammatory treatment with pentoxifylline (PTX). Flow‐mediated dilation (FMD) was evaluated for 8 weeks in 9 HIV‐infected patients treating with PTX 400mg. Recombinant IFN‐γ and TNF‐α, either alone or together with HIV‐TAT protein was added to primary human endothelial cells in vitro. Endothelial cells were also treated with the anti‐inflammatory PTX to assess modulation of IP‐10 and VCAM‐1for gene expression through qRT‐PCR, and protein production by ELISA or using immunofluorescence. We demonstrate that HIV‐1 positive patients have decreased endothelial function as assessed by FMD compared with HIV‐1 negative patients, and that FMD can be improved by treating with PTX. In vitro, the expression levels of IP‐10 and VCAM‐1 genes in endothelial cells were significantly enhanced by HIV‐TAT when combined with IFN‐γ or TNF‐α, respectively and were significantly reduced by co‐treatment with PTX. Similarly, protein production of IP‐10 and VCAM‐1 was also increased by HIV‐TAT in combination with IFN‐γ or TNF‐α treatment, respectively, compared with single IFN‐γ or TNF‐α treatment, and significantly reduced by PTX. These results extend our understanding of the roles of HIV and systemic inflammatory mediators on endothelial inflammation and may explain the beneficial effects of PTX on endothelial function in HIV patients.