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

Abstract

Background: 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. Methods: Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3 −/−) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) in vivo] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10 −6 M, 2 h) in vitro]. 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. Results: Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both in vivo and in vitro. These effects were not observed in arteries from NLRP3 −/− mice. Aortas of TP-treated WT mice (in vivo), as well as aortas from WT mice incubated with testo (in vitro), 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 −5 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10 −6 M, mitochondrial uncoupler) and MCC950 (MCC950, 10 −6 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Conclusion: Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.

Sex-Specific Signature in the Circulating NLRP3 Levels of Saudi Adults with Metabolic Syndrome

“…Further analysis of circulating NLRP3 levels between pre- and post-menopausal women in this study was not possible due to low sample size in post-menopausal group; hence, future large studies on this subject would reveal this distinction in a better manner. Progesterone and androgens such as testosterone, on the other hand, have been linked with NLRP3 inflammasome activation [ 50 ]; however, this role of the male sex hormone needs further elucidation, as there are reports which conflict with the assisting role of testosterone for NLRP3 inflammasome activation [ 51 ]. Nonetheless, the sex-specific signature observed here in the circulating levels of NLRP3 proteins suggests its active role in the pathogenesis of MetS.…”

Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients

“…For example, testosterone can directly activate NLRP3 inflammasome and mediate fibrosis in a CCl4-induced liver injury model (Ma et al, 2020). Excess testosterone production, which exceeds its normal range, can induce mitochondrial ROS to indirectly activate NLRP3 inflammasome (Alves et al, 2020). On the other hand, estrogen plays a more complicated role in regulating NLRP3 inflammasome activation.…”

An update on the regulatory mechanisms of NLRP3 inflammasome activation

“… 133 Human respiratory syncytial virus (RSV) infection triggers macrophage cell lysis through NLRP3 inflammasome-mediated pyroptosis through ROS production 134 Moreover, supraphysiological testosterone levels trigger vascular dysfunction through induction of mtROS generation, enhancing NLRP3 inflammasome activation and leading to increased cardiovascular risk. 135 In summary, multiple danger or microbial signals are involved in triggering mtROS generation to further activate the NLRP3 inflammasome.…”