TY - JOUR
T1 - Hiv protease inhibitor ritonavir impairs endothelial function via reduction in adipose mass and endothelial leptin receptor-dependent increases in nadph oxidase 1 (Nox1), c-c chemokine receptor type 5 (ccr5), and inflammation
AU - Bruder-Nascimento, Thiago
AU - Kress, Taylor C.
AU - Kennard, Simone
AU - Belin de Chantemèle, Eric J.
N1 - Funding Information:
This work was supported by a Postdoctoral Fellowship (17POST33410363), a K99 (1K99HL140139-01A1), and a R00 (4R00HL14013903) from the NHLBI to Bruder-Nascimento. This study was also supported by an Established Investigator Award (19EIA34760167) from the American Heart Association, R01s (1R01HL130301-01 and 1R01HL147639-01A1) from the NHLBI, and Start-up funds from Augusta University to Belin de Chantemèle.
Publisher Copyright:
© 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2020/10/6
Y1 - 2020/10/6
N2 - BACKGROUND: Cardiovascular disease is currently the leading cause of death in patients with human immunodeficiency virus on combination antiretroviral therapy. Although the use of the protease inhibitor ritonavir has been associated with increased prevalence of cardiovascular disease, the underlying mechanisms remain ill-defined. Herein, we tested the hypothesis that ritonavir-mediated lipoatrophy causes endothelial dysfunction via reducing endothelial leptin signaling. METHODS AND RESULTS: Long-term (4 weeks) but not short-term (3 days) treatment with ritonavir reduced body weight, fat mass, and leptin levels and induced endothelial dysfunction in mice. Moreover, ritonavir increased vascular NADPH oxidase 1, aortic H2 O2 levels as well as interleukin-1β, GATA3 (GATA binding protein 3), the macrophage marker (F4/80), and C-C chemokine receptor type 5 (CCR5) expression. Reactive oxygen species scavenging with tempol restored endothelial func-tion, and both NADPH oxidase 1 and CCR5 deletion in mice protected from ritonavir-mediated endothelial dysfunction and vascular inflammation. Remarkably, leptin infusion markedly improved endothelial function and significantly reduced vascular NADPH oxidase 1, interleukin-1β, GATA3, F4/80, and CCR5 levels in ritonavir-treated animals. Selective deficiency in endothelial leptin receptor abolished the protective effects of leptin infusion on endothelial function. Conversely, selective increases in endothelial leptin signaling with protein tyrosine phosphatase deletion blunted ritonavir-induced endothelial dysfunction. CONCLUSIONS: All together, these data indicate that ritonavir-associated endothelial dysfunction is a direct consequence of a reduction in adiposity and leptin secretion, which decreases endothelial leptin signaling and leads to a NADPH oxidase 1– induced, CCR5-mediated reduction in NO bioavailability. These latter data also introduce leptin deficiency as an additional contributor to cardiovascular disease and leptin as a negative regulator of CCR5 expression, which may provide beneficial avenues for limiting human immunodeficiency virus infection.
AB - BACKGROUND: Cardiovascular disease is currently the leading cause of death in patients with human immunodeficiency virus on combination antiretroviral therapy. Although the use of the protease inhibitor ritonavir has been associated with increased prevalence of cardiovascular disease, the underlying mechanisms remain ill-defined. Herein, we tested the hypothesis that ritonavir-mediated lipoatrophy causes endothelial dysfunction via reducing endothelial leptin signaling. METHODS AND RESULTS: Long-term (4 weeks) but not short-term (3 days) treatment with ritonavir reduced body weight, fat mass, and leptin levels and induced endothelial dysfunction in mice. Moreover, ritonavir increased vascular NADPH oxidase 1, aortic H2 O2 levels as well as interleukin-1β, GATA3 (GATA binding protein 3), the macrophage marker (F4/80), and C-C chemokine receptor type 5 (CCR5) expression. Reactive oxygen species scavenging with tempol restored endothelial func-tion, and both NADPH oxidase 1 and CCR5 deletion in mice protected from ritonavir-mediated endothelial dysfunction and vascular inflammation. Remarkably, leptin infusion markedly improved endothelial function and significantly reduced vascular NADPH oxidase 1, interleukin-1β, GATA3, F4/80, and CCR5 levels in ritonavir-treated animals. Selective deficiency in endothelial leptin receptor abolished the protective effects of leptin infusion on endothelial function. Conversely, selective increases in endothelial leptin signaling with protein tyrosine phosphatase deletion blunted ritonavir-induced endothelial dysfunction. CONCLUSIONS: All together, these data indicate that ritonavir-associated endothelial dysfunction is a direct consequence of a reduction in adiposity and leptin secretion, which decreases endothelial leptin signaling and leads to a NADPH oxidase 1– induced, CCR5-mediated reduction in NO bioavailability. These latter data also introduce leptin deficiency as an additional contributor to cardiovascular disease and leptin as a negative regulator of CCR5 expression, which may provide beneficial avenues for limiting human immunodeficiency virus infection.
KW - CCR5
KW - HIV
KW - Leptin
KW - Lipoatrophy
KW - NADPH oxidase
KW - Ritonavir
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U2 - 10.1161/JAHA.120.018074
DO - 10.1161/JAHA.120.018074
M3 - Article
C2 - 33003981
AN - SCOPUS:85092677574
SN - 2047-9980
VL - 9
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 19
M1 - e018074
ER -