NLRP3 activation contributes to endothelin-1-induced erectile dysfunction

Author(s)

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

• Document type: Journal article
• Source: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE; v. 27, n. 1, p. 14-pg., 2022-12-14.

Abstract

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)

• FAPESP's process: 16/07641-0 - The NLRP3 role in erectile dysfunction in hypertensive model DOCA / salt and its possible activation by ET-1
• Grantee: Rafael Sobrano Fais
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/05638-7 - The Role Of Calcium-Activated Potassium Channels 2.3 (KCa 2.3) In The Inhibition Of Endothelin-1 (ET-1)-Induced NLRP3 Activation And Impairment Of The Erectile Function In DOCA/Salt Model Of Arterial Hypertension
• Grantee: Rafael Sobrano Fais
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 16/11988-5 - NLRP3 contribution to the pro-inflammatory effect of ET-1 in corpora cavernosa smooth muscle cells: relevance in erectile function.
• Grantee: Fernando Silva Carneiro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/19749-8 - Erectile dysfunction induced by high fat diet: the role of TNF-alpha
• Grantee: Fernando Silva Carneiro
• Support Opportunities: Regular Research Grants