TY - JOUR
T1 - Chronic exposure to HIV-derived protein TAT impairs endothelial function via indirect alteration in fat mass and Nox1-mediated mechanisms in mice
AU - Kovacs, Laszlo
AU - Bruder-Nascimento, Thiago
AU - Greene, Lindsey
AU - Kennard, Simone
AU - De Chantemèle, Eric J.Belin
N1 - Funding Information:
Author Contributions: Conception, design, experiment, analysis and interpretation, L.K., T.B.-N., and E.J.B.d.C.; L.G.and S.K. participated in the animal work. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by a K99 (1K99HL140139-01A1), and a R00 (4R00HL14013903) fFruonmdtihneg:NTHhLisB IwtoorkT BwNa.s Tsuhpispsotruteddy bwya as Kal9so s9u (p1pKo9r9teHdLb1y40a1n3E9s-t0a1bAli1s)h, eadndIn vae sRt0ig0a (t4oRr0A0wHaLr1d4013903) from the NHLBI to TBN. This study was also supported by an Established Investigator Award (19EIA34760167) from theAmerican HeartAssociation, R01s (1R01HL155265, 1R01HL130301, and Institutional1R01HL147639) from the NHReview Board Statement:LBI to EBdC. All procedures and protocols were approved by the Augusta
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/2
Y1 - 2021/10/2
N2 - 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.
AB - 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.
KW - Endothelial dysfunction
KW - HIV Tat protein
KW - Leptin
KW - Nox1
UR - http://www.scopus.com/inward/record.url?scp=85117055349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117055349&partnerID=8YFLogxK
U2 - 10.3390/ijms222010977
DO - 10.3390/ijms222010977
M3 - Article
C2 - 34681637
AN - SCOPUS:85117055349
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 20
M1 - 10977
ER -