NLRP3 contribution to the pro-inflammatory effect of ET-1 in corpora cavernosa smooth muscle cells: relevance in erectile function.

• Grant number: 16/11988-5
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2016 - August 31, 2018
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Fernando Silva Carneiro
• Grantee: Fernando Silva Carneiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide secreted by vascular endothelial cells. After its initial discovery, it has become more evident that ET-1 is involved in several pathophysiological processes other than just controlling vascular tone, such as remodelling, fibrosis, apoptosis, hypertrophy and inflammation. Therefore, ET-1 system imbalances has been associated to different diseases, such as systemic arterial hypertension, pulmonary arterial hypertension, hypertrophy and heart failure and renal diseases. Likewise the cardiovascular system, cavernosal smooth muscle cells (CSMC) not only respond to ET-1, but also synthesize it. In addition, ET-1 system is involved in erectile dysfunction (ED) in humans and experimental models. A close association between ED and a low-grade inflammatory process has been demonstrated consistently in several studies. It is thought that the increased inflammatory mediators is the common pathophysiological mechanism between ED and cardiovascular diseases. Beyond its potent vasoconstrictor capacity, ET-1 displays pro-inflammatory properties implicated in the pathophysiology of many cardiovascular diseases. Although ET-1 pro-inflammatory effects are largely demonstrated in the literature, the responsible mechanisms triggered by ET-1 in the penile erection system are completely unknown. NLRP3 is an innate immune system receptor responsible by recognizing intracellular pathogens as well as released endogenous substances during cell damage and tissue injury. NLRP3 is involved in chronic inflammatory processes and plays an important role in atherosclerosis, myocardial injury after ischemia/reperfusion, chronic renal disease and arterial hypertension. Based on that, the present study hypothesizes that NLRP3 mediates ET-1 pro-inflammatory effects in CSMC. Increased inflammatory mediators, in turn, impairs cavernosal smooth muscle and penile vasculature reactivity and favours ED development in DOCA-salt hypertension model (model that displays increased ET-1). To test our central hypothesis, the present study will investigate two corollaries of the hypothesis: 1) To test the hypothesis that NLRP3 mediates ET-1 pro-inflammatory effects in CSMC and also its possible mechanisms; This first part will determine whether ET-1 increases NLRP3 activity in CSMC, as well as the signalling pathway downstream to ET-1 receptor activation. 2) To tests the hypothesis that NLRP3 mediates ET-1-induced pro-inflammation in DOCA-salt hypertension model-associated ED; This second part will determine, as a concept proof, whether NLRP3 contributes to ET-1-induced inflammation in the hypertensive experimental model DOCA-salt, which displays ED associated to increased ET-1. (AU)

Scientific publications

(5)

(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)

BOMFIM, GISELE F.; RODRIGUES, FERNANDA LUCIANO; CARNEIRO, FERNANDO S.. Are the innate and adaptive immune systems setting hypertension on fire?. PHARMACOLOGICAL RESEARCH, v. 117, p. 377-393, MAR 2017. (15/21976-1, 10/17362-4, 16/11988-5)

RODRIGUES, FERNANDA LUCIANO; FAIS, RAFAEL S.; PEREIRA, MARLIA G. A. G.; GARCIA-CAIRASCO, NORBERTO; TOSTES, RITA C.; CARNEIRO, FERNANDO S.. Erectile Dysfunction in Wistar Audiogenic Rats Is Associated With Increased Cavernosal Contraction and Decreased Neuronal Nitric Oxide Synthase Protein Expression. UROLOGY, v. 106, AUG 2017. (10/17362-4, 15/21976-1, 05/56447-7, 16/11988-5)

FREITAS, RAIANY A.; JUNIOR, RINALDO R. P.; JUSTINA, VANESSA D.; BRESSAN, ALECSANDER F. M.; BOMFIM, GISELE F.; CARNEIRO, FERNANDO S.; GIACHINI, FERNANDA R.; LIMA, VICTOR V.. Angiotensin (1-7)-attenuated vasoconstriction is associated with the Interleukin-10 signaling pathway. Life Sciences, v. 262, DEC 1 2020. (16/11988-5)

BOMFIM, GISELE FACHOLI; ASSIS CAU, STEFANY BRUNO; BRUNO, ALEXANDRE SANTOS; FEDOCE, ALINE GARCIA; CARNEIRO, FERNANDO S.. Hypertension: a new treatment for an old disease? Targeting the immune system. British Journal of Pharmacology, v. 176, n. 12, SI, p. 2028-2048, JUN 2019. (16/11988-5)

DAS GRACAS CORSI-ZUELLI, FABIANA MARIA; BROGNARA, FERNANDA; DA SILVA QUIRINO, GUSTAVO FERNANDO; HIROKI, CARLOS HIROJI; FAIS, RAFAEL SOBRANO; DEL-BEN, CRISTINA MARTA; ULLOA, LUIS; SALGADO, HELIO CESAR; KANASHIRO, ALEXANDRE; LOUREIRO, CAMILA MARCELINO. Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Acetylcholine the Alpha-7 nicotinic Acetylcholine Receptor. FRONTIERS IN IMMUNOLOGY, v. 8, MAY 31 2017. (12/05178-0, 16/12195-9, 13/20549-7, 11/20343-4, 16/07641-0, 16/11988-5, 15/10378-6)