Abstract
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.
Highlights
Published: 12 October 2021Currently, more than 37 million people are infected with human immunodeficiency virus (HIV) globally [1]
In order to investigate whether Tat mediates HIV-associated endothelial dysfunction, male mice were submitted to 4 weeks of Tat treatment
We found that chronic treatment with Tat markedly reduced body weight (Figure 1A), subcutaneous (Figure 1B), visceral adipose tissue mass (Figure 1C), and plasma leptin levels (Figure 1D) in WT mice
Summary
More than 37 million people are infected with human immunodeficiency virus (HIV) globally [1]. Successful use of combination antiretroviral therapy (cART) has contributed to a significant reduction in HIV/AIDS-related events [2]. People infected with HIV are living much longer, but are exposed to increased risk of non-AIDS-associated chronic illnesses, including cardiovascular disease (CVD) [3]. CVD is the leading cause of morbidity and mortality in people living with HIV (PLWH). On cART [4,5,6]. A growing body of evidence indicates that vascular endothelial function is impaired in PLWH [8,9], the underlying mechanisms leading to the development of HIV-associated endothelial dysfunction are not completely understood
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