Browsing by Subject "Vascular Disease"

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    HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction Implications for Statin Treatment in HIV Patients
    (American Heart Association, 2019-08-27) Chelvanambi, Sarvesh; Gupta, Samir K.; Chen, Xingjuan; Ellis, Bradley W.; Maier, Bernhard F.; Colbert, Tyler M.; Kuriakose, Jithin; Zorlutuna, Pinar; Jolicoeur, Paul; Obukhov, Alexander G.; Clauss, Matthias; Medicine, School of Medicine
    Rationale Even in antiretroviral therapy (ART) treated patients, HIV continues to play a pathogenic role in cardiovascular diseases. A possible cofactor may be persistence of the early HIV response gene Nef, which we have demonstrated recently to persist in the lungs of HIV+ patients on ART. Previously, we have reported that HIV strains with Nef, but not Nef-deleted HIV strains, cause endothelial proinflammatory activation and apoptosis. Objective To characterize mechanisms through which HIV-Nef leads to the development of cardiovascular diseases using ex vivo tissue culture approaches as well as interventional experiments in transgenic murine models. Methods and Results EV (extracellular vesicles) derived from both peripheral blood mononuclear cells (PBMC) and plasma from HIV+ patient blood samples induced human coronary artery endothelial cells dysfunction. Plasma derived EV from ART+ patients that were HIV-Nef+ induced significantly greater endothelial apoptosis compared to HIV-Nef- plasma EV. Both HIV-Nef expressing T cells and HIV-Nef-induced EV increased transfer of cytosol and Nef protein to endothelial monolayers in a Rac1-dependent manner, consequently leading to endothelial adhesion protein upregulation and apoptosis. HIV-Nef induced Rac1 activation also led to dsDNA breaks in endothelial colony forming cells (ECFC), thereby resulting in ECFC premature senescence and eNOS downregulation. These Rac1 dependent activities were characterized by NOX2-mediated ROS production. Statin treatment equally inhibited Rac1 inhibition in preventing or reversing all HIV-Nef-induction abnormalities assessed. This was likely due to the ability of statins to block Rac1 prenylation as geranylgeranyl transferase inhibitors were effective in inhibiting HIV-Nef-induced ROS formation. Finally, transgenic expression of HIV-Nef in endothelial cells in a murine model impaired endothelium-mediated aortic ring dilation, which was then reversed by 3-week treatment with 5mg/kg atorvastatin. Conclusion These studies establish a mechanism by which HIV-Nef persistence despite ART could contribute to ongoing HIV related vascular dysfunction which may then be ameliorated by statin treatment.