Journal Article

Chronic Exposure to HIV-Derived Protein Tat Impairs Endothelial Function via Indirect Alteration in Fat Mass and Nox1-Mediated Mechanisms in Mice

Kovacs, Laszlo, Bruder-Nascimento, Thiago, Belin de Chantemèle, Eric J., Kennard, Simone, Greene, Lindsey

2021

Overview

People living with human immunodeficiency virus (HIV) (PLWH) have increased risk for atherosclerosis-related cardiovascular disease (CVD), the main cause of death in this population. Notwithstanding, the mechanisms of HIV-associated vascular pathogenesis are not fully elucidated. Therefore, we sought to determine whether HIV-regulatory protein Tat mediates HIV-induced endothelial dysfunction via NADPH oxidase 1 (Nox1)-dependent mechanisms. Body weight, fat mass, leptin levels, expression of reactive oxygen species (ROS)-producing enzymes and vascular function were assessed in C57BL/6 male mice treated with Tat for 3 days and 4 weeks. Aortic rings and human endothelial cells were also treated with Tat for 2–24 h in ex vivo and in vitro settings. Chronic (4 weeks) but not acute (3 days and 2–24 h) treatment with Tat decreased body weight, fat mass, and leptin levels and increased the expression of Nox1 and its coactivator NADPH oxidase Activator 1 (NoxA1). This was associated with impaired endothelium-dependent vasorelaxation. Importantly, specific inhibition of Nox1 with GKT771 and chronic leptin infusion restored endothelial function in Tat-treated mice. These data rule out direct effects of HIV-Tat on endothelial function and imply the contribution of reductions in adipose mass and leptin production which likely explain upregulated expression of Nox1 and NoxA1. The Nox1 and leptin system may provide potential targets to improve vascular function in HIV infection-associated CVD.

• Publisher: MDPI AG,MDPI
• Subject: Acquired immune deficiency syndrome / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adipose Tissue - drug effects / Adipose Tissue - physiology / AIDS / Animals / Body Weight - drug effects / Endothelium, Vascular - drug effects / Endothelium, Vascular - metabolism / HIV / Human immunodeficiency virus / Human Umbilical Vein Endothelial Cells / Humans / Leptin - blood / Leptin - pharmacology / Male / Mice / Mice, Inbred C57BL / NADPH Oxidase 1 - antagonists & inhibitors / NADPH Oxidase 1 - genetics / NADPH Oxidase 1 - metabolism / Nitric oxide / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal Transduction - drug effects / tat Gene Products, Human Immunodeficiency Virus - pharmacology / Viral infections