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

Grant number: 19/20692-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2020
Effective date (End): January 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Juliano Vilela Alves
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
Associated scholarship(s):22/00103-3 - The role of supraphysiological levels of testosterone on NOX5-dependent generation of reactive oxygen species in human endothelial cells, BE.EP.DR


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)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALVES, JULIANO V.; COSTA, RAFAEL M.; OMOTO, ANA C. M.; OLIVEIRA-NETO, JOSE T.; SILVA, JOSIANE F.; MACHADO, MIRELE R.; ROSA, UALTER G.; BONATO, VANIA L. D.; TOSTES, RITA C. A.. Supraphysiological Levels of Testosterone Induce Cardiac Dysfunction via NLRP3 Inflammasome Activation in Macrophages. FASEB JOURNAL, v. 36, p. 2-pg., . (19/20692-0)

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