Involvement of the NLRP3 inflammasome in cardiac dysfunction associated with supraphysiological levels of testosterone

Abstract

Increased testosterone levels are associated with cardiovascular risk factors, including abdominal Obesity and Hypertension, as well as Cardiovascular Diseases (CVD). Testosterone modulates vascular tone and cardiac performance, as well as components involved in redox and inflammatory processes, including Reactive Oxygen Species (ROS) and proinflammatory cytokines. The inflammasome NLRP3, a component of the innate immune system, is an important regulator of chronic inflammation. Its activation is mediated by damage/injury-associated molecular patterns (DAMPs) and leads to pro-inflammatory cytokines production. Activation of the NLRP3 inflammasome contributes to cardiac hypertrophy and renal injury in experimental models of Hypertension. Considering that testosterone stimulates the production of DAMPs, the present study will test the hypothesis that supraphysiological testosterone levels activate the NLRP3 inflammasome complex in immune system cells and in cardiomyocytes, resulting in cytokines release, inflammatory process and, consequently, cardiac dysfunction. To test our hypothesis, we will use wild type and knockout mice for NLRP3 (NLRP3-/-), ASC (ASC-/-), Caspase-1 (Casp1-/-) and IL-1² (IL-1²-/-) proteins. Mice will be treated with testosterone propionate (10 mg/kg for 30 days) and assays will be performed to assess cardiac function and structure, as well as cellular and molecular mechanisms that lead to NLRP3 inflammasome activation. (AU)