Participation of IL-17 in vascular hypercontractility induced by ethanol consumption: associated mechanisms

• Grant number: 25/13579-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Luisa Carrera Giacomelli
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 24/15661-7 - The role of IL-17 in the loss of the anticontractile effect of perivascular adipose tissue and of IL-6 in the polarization of naïve T lymphocytes to the Th17 phenotype during ethanol consumption, AP.R

Abstract

Ethanol consumption is a risk factor for the development of cardiovascular diseases, such as arterial hypertension. Ethanol promotes functional changes in the vasculature that are associated with vascular hypercontractility. This response is identified as one of the mechanisms by which ethanol consumption increases blood pressure. The pro-contractile effect of ethanol is multimediated and involves an increase in the production of reactive oxygen species (ROS) by the enzyme NADPH oxidase and induction of cyclooxygenase (COX)2, with consequent formation of vasoconstrictor prostanoids such as thromboxane (TX)A2 and prostaglandin (PG)E2. In addition, ethanol consumption increases circulating concentrations of pro-inflammatory cytokines that contribute to the process of vascular dysfunction induced by ethanol. IL-17 is a cytokine produced mainly by T helper-17 (Th17) lymphocytes. It acts through different receptors, with IL-17RA being the main mediator of its biological actions.This cytokine is considered an important mediator of vascular dysfunction in different pathophysiological conditions, in which it induces damage to the vasculature by multiple mechanisms, including the production of ROS and reduced bioavailability of nitric oxide (NO). It is worth mentioning that IL-17 acts as a mediator of the deleterious actions of ethanol in different tissues, including the liver, lung, skin, and intestine. Finally, clinical and experimental studies have shown that ethanol consumption is associated with increased IL-17. However, the literature is scarce regarding the involvement of this cytokine in cardiovascular damage induced by ethanol consumption.Thus, the hypothesis of the present study is that ethanol will promote an increase in IL-17, which, via IL-17RA, will induce COX2, with a consequent increase in vasoconstrictor prostanoids (TXA2 and PGE2), in addition to activating the enzyme NADPH oxidase, thus increasing the generation of O2*-. Together, these responses will lead to vascular hypercontractility. The study was designed with the objective of verifying the contribution of IL-17 to the pro-contractile effect of ethanol, evaluating the production of O2*- (via NADPH oxidase) and the induction of COX2 as intracellular mechanisms. It is expected that in knockout mice for the IL-17RA receptor there will be a reduction in: 1. production of O2*-; 2. activity and expression of NADPH oxidase; 3. expression of COX2; 4. production of TXA2 and PGE2 (vasoconstrictor prostanoids); 5. vascular hypercontractility. For this purpose, male C57Bl6 mice (Wild Type; WT) will be treated with ethanol solution for 12 weeks. The participation of IL-17 in vascular dysfunction will be evaluated using IL-17RA knockout mice (IL-17RA-/-; B6.Cg-Il17ratm2.2Koll/J). Functional (vascular reactivity) and molecular (ELISA, Western immunoblotting, colorimetry) evaluations will be performed using blood and thoracic aorta. (AU)