AUTHOR=Robles-Vera Iñaki , Toral Marta , de la Visitación Néstor , Aguilera-Sánchez Nazaret , Redondo Juan Miguel , Duarte Juan 

TITLE=Protective Effects of Short-Chain Fatty Acids on Endothelial Dysfunction Induced by Angiotensin II

JOURNAL=Frontiers in Physiology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00277

DOI=10.3389/fphys.2020.00277

ISSN=1664-042X

ABSTRACT=Short-chain fatty acids (SCFAs) are a major class of bacterial metabolites and are mainly produced in the colon by bacterial fermentation. SCFAs such as acetate, butyrate and propionate, reduce endothelial activation induced by pro-inflammatory mediators, at least in part, by activation of G protein-coupled receptors (GPRs): GPR41 and GPR43. The aim of this study was to analyze the possible protective effects of SCFAs on endothelial dysfunction induced by angiotensin II (AngII). Rat aortic endothelial cells (RAECs) and rat aortas were incubated with AngII (1 μM) for 6 h in the presence or absence of SCFAs (5-10 mM). In RAECs we found that AngII reduces the production of nitric oxide (NO) stimulated by calcium ionophore A23187, increases the production of reactive oxygen species (ROS), both from the NADPH oxidase system and the mitochondria, diminished vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser239, reduced GPR41 and GPR43 mRNA level, and reduces the endothelium-dependent relaxant response to acetylcholine in aorta. Co-incubation with butyrate and acetate, but not with propionate, increases both NO production and pSer239-VASP, reduces the concentration of intracellular ROS and improves relaxation to acetylcholine. The beneficial effects of butyrate were inhibited by the GPR41 receptor antagonist, β-hydroxybutyrate, and by the GPR43 receptor antagonist, GLPG0794. Butyrate inhibited the down-regulation of GPR41 and GPR43 induced by AngII, being without effect acetate and propionate. Neither β-hydroxybutyrate nor GLPG0794 affect the protective effect of acetate in endothelial dysfunction. In conclusion, acetate and butyrate improve endothelial dysfunction induced by AngII by increasing the bioavailability of NO. The effect of butyrate seems to be related to GPR41/43 activation, whereas acetate effects were independent of GPR41/43.