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NLRP3 activation contributes to endothelin-1-induced erectile dysfunction

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WILEY
DOI: 10.1111/jcmm.17463

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corpus cavernosum; erectile dysfunction; ET-1; inflammation; NLRP3

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In this study, it was hypothesized that stimulation of endothelin receptors ETA and ETB leads to NLRP3 activation through increased calcium and ROS formation. The experiments conducted on mice demonstrated that ET-1 reduced intracavernosal pressure and the CC ACh and SNP-induced relaxation, while increasing caspase-1 expression. The use of receptor antagonists, genetic deletion, and ROS inhibitors reversed these effects, indicating that ET-1-induced erectile dysfunction involves the activation of NLRP3 via Ca2+-dependent ROS generation mediated by ETA- and ETB-receptors.
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.

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