NLRP3 activation contributes to endothelin-1-induced erectile dysfunction

Autor(es)

Sobrano Fais, Rafael ; Menezes da Costa, Rafael ; Carvalho Mendes, Allan ; Mestriner, Fabiola ; Comerma-Steffensen, Simon Gabriel ; Tostes, Rita C. ; Simonsen, Ulf ; Silva Carneiro, Fernando

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE; v. 27, n. 1, p. 14-pg., 2022-12-14.

Resumo

In the present study, we hypothesized that endothelin (ET) receptors (ETA and ETB) stimulation, through increased calcium and ROS formation, leads to Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3 (NLRP3) activation. Intracavernosal pressure (ICP/MAP) was measured in C57BL/6 (WT) mice. Functional and immunoblotting assays were performed in corpora cavernosa (CC) strips from WT, NLRP3(-/-) and caspase(-/-) mice in the presence of ET-1 (100 nM) and vehicle, MCC950, tiron, BAPTA AM, BQ123, or BQ788. ET-1 reduced the ICP/MAP in WT mice, and MCC950 prevented the ET-1 effect. ET-1 decreased CC ACh-, sodium nitroprusside (SNP)-induced relaxation, and increased caspase-1 expression. BQ123 an ETA receptor antagonist reversed the effect. The ETB receptor antagonist BQ788 also reversed ET-1 inhibition of ACh and SNP relaxation. Additionally, tiron, BAPTA AM, and NLRP3 genetic deletion prevented the ET-1-induced loss of ACh and SNP relaxation. Moreover, BQ123 diminished CC caspase-1 expression, while BQ788 increased caspase-1 and IL-1 beta levels in a concentration-dependent manner (100 nM-10 mu M). Furthermore, tiron and BAPTA AM prevented ET-1-induced increase in caspase-1. In addition, BAPTA AM blocked ET-1-induced ROS generation. In conclusion, ET-1-induced erectile dysfunction depends on ETA- and ETB-mediated activation of NLRP3 in mouse CC via Ca2+-dependent ROS generation. (AU)

• Processo FAPESP: 16/07641-0 - Papel do NLRP3 na disfunção erétil em modelo de hipertensão DOCA/sal e sua possível ativação por ET-1
• Beneficiário: Rafael Sobrano Fais
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/05638-7 - O Papel Inibitório Dos Canais para Potássio Ativados Por Cálcio 2,3 (KCa 2,3) Na Ativação do NLRP3 Induzida Pela Endotelina-1 (ET-1) E No Prejuízo Da Função Erétil Em Modelo de Hipertensão DOCA/Sal
• Beneficiário: Rafael Sobrano Fais
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 16/11988-5 - Contribuição do NLRP3 para o efeito pró-inflamatório da ET-1 em células de músculo liso do corpo cavernoso: relevância na função erétil.
• Beneficiário: Fernando Silva Carneiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/19749-8 - Disfunção erétil na Obesidade induzida por dieta hiperlipídica: papel do TNF-alfa
• Beneficiário: Fernando Silva Carneiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular