Chronic Exposure to HIV-Derived Protein Tat Impairs Endothelial Function via Indirect Alteration in Fat Mass and Nox1-Mediated Mechanisms in Mice.
Laszlo KovacsThiago Bruder-NascimentoLindsey GreeneSimone KennardEric J Belin de ChantemèlePublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- human immunodeficiency virus
- antiretroviral therapy
- reactive oxygen species
- hiv positive
- hiv infected
- hepatitis c virus
- body weight
- hiv testing
- hiv aids
- endothelial cells
- cardiovascular disease
- poor prognosis
- men who have sex with men
- adipose tissue
- south africa
- binding protein
- type diabetes
- drug induced
- low dose
- cell death
- fatty acid
- liver failure
- heart failure
- metabolic syndrome
- oxidative stress
- coronary artery disease
- transcription factor
- cardiovascular events
- big data
- high fat diet induced
- data analysis
- smoking cessation
- amino acid