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NLRP3 activation contributes to Endothelin-1-induced erectile dysfunction
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  • Rafael Fais,
  • Rafael Menezes da Costa,
  • Allan Carvalho Mendes,
  • Fabiola Antunes Cardoso Mestriner,
  • Simon Comerma-Steffensen,
  • Rita Tostes,
  • Ulf Simonsen,
  • Fernando Carneiro
Rafael Fais
Indiana University School of Medicine
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Rafael Menezes da Costa
Federal University of Jataí
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Allan Carvalho Mendes
University of Sao Paulo Faculty of Medicine of Ribeirao Preto
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Fabiola Antunes Cardoso Mestriner
University of Sao Paulo Faculty of Medicine of Ribeirao Preto
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Simon Comerma-Steffensen
Aarhus Universitet
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Rita Tostes
University of Sao Paulo
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Ulf Simonsen
University of Aarhus
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Fernando Carneiro
Universidade de Sao Paulo Faculdade de Medicina de Ribeirao Preto
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Abstract

Background and Purpose: Endothelin-1 (ET-1) and Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3 (NLRP3) play an essential role in erectile dysfunction. ET-1 and NLRP3 activate inflammatory processes by increasing calcium (Ca2+) and reactive oxygen species (ROS). In the present study, we hypothesized that endothelin receptors (ETA and ETB) stimulation, through increased calcium and ROS formation, leads to NLRP3 activation. Experimental approach: 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 after ET-1 (100 nM) stimulation in the presence of vehicle, MCC950, tiron, BAPTA AM, BQ123, or BQ788. Key Results: ET-1 gradually reduced the ICP/MAP in WT mice, and MCC950 administration prevented the effect of ET-1. ET-1 decreased CC relaxation to ACh and sodium nitroprusside (SNP) and increased caspase-1 protein expression, effects reversed by the ETA receptor antagonist BQ123. The ETB receptor antagonist BQ788 also reversed the effect of ET-1 on 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-1β levels in a concentration-dependent manner (100 nM to 10 µM). Furthermore, tiron and BAPTA AM prevented ET-1-induced increase in caspase-1. In addition, BAPTA AM blocked ET-1-induced ROS generation. Conclusion and Implications: NLRP3 activation contributes to acute ET-1-induced erectile dysfunction by mechanisms that depend on ETA- and ETB-induced Ca2+ influx and ROS generation.