Journal Article

Supraphysiological Levels of Testosterone Induce Vascular Dysfunction via Activation of the NLRP3 Inflammasome

Pereira, Camila André, Silva, Carlos Alberto Aguiar, da Costa, Rafael Menezes, Lobato, Núbia Souza, Tostes, Rita C., Alves, Juliano Vilela, Fedoce, Aline Garcia, Carneiro, Fernando Silva

2020

Overview

Both supraphysiological and subphysiological testosterone levels are associated with increased cardiovascular risk. Testosterone consumption at supraphysiological doses has been linked to increased blood pressure, left ventricular hypertrophy, vascular dysfunction, and increased levels of inflammatory markers. Activation of the NLRP3 inflammasome contributes to the production of proinflammatory cytokines, leading to cardiovascular dysfunction. We hypothesized that supraphysiological levels of testosterone, via generation of mitochondrial reactive oxygen species (mROS), activates the NLRP3 inflammasome and promotes vascular dysfunction. Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3 ) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) ] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10 M, 2 h) ]. Testosterone levels, blood pressure, vascular function (thoracic aortic rings), pro-caspase-1/caspase-1 and interleukin-1β (IL-1β) expression, and generation of reactive oxygen species were determined. Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both and . These effects were not observed in arteries from NLRP3 mice. Aortas of TP-treated WT mice ( ), as well as aortas from WT mice incubated with testo ( ), exhibited increased mROS levels and increased caspase-1 and IL-1β expression. These effects were not observed in arteries from NLRP3 mice. Flutamide [Flu, 10 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10 M, mitochondrial uncoupler) and MCC950 (MCC950, 10 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: androgen receptor / Androgen receptors / Androgens / Androgens - toxicity / Animals / Aorta, Thoracic - drug effects / Aorta, Thoracic - metabolism / Aorta, Thoracic - physiopathology / Apoptosis / Arteries / Blood levels / Blood pressure / Bodybuilding / Cardiovascular disease / Cardiovascular diseases / Caspase 1 - metabolism / Caspase-1 / Chemokines / Contractility / Cytokines / Endothelium / Enzymes / Flutamide / Heart / Hypertrophy / IL-1β / Immunology / Inflammasomes / Inflammasomes - agonists / Inflammasomes - genetics / Inflammasomes - metabolism / Interleukin-1beta - metabolism / Leukocytes / Male / Mice, Inbred C57BL / Mice, Knockout / Mitochondria - drug effects / Mitochondria - metabolism / NLR Family, Pyrin Domain-Containing 3 Protein - agonists / NLR Family, Pyrin Domain-Containing 3 Protein - deficiency / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / NLRP3 inflammasome / Potassium / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / Receptors, Androgen - drug effects / Receptors, Androgen - metabolism / Steroids / Testosterone / Testosterone propionate / Testosterone Propionate - toxicity / Thorax / Tissue Culture Techniques / vascular dysfunction / Vasoconstriction - drug effects / Vasodilation / Vasodilation - drug effects