Robles-Vera Iñaki, Toral Marta, de la Visitación Néstor, Aguilera-Sánchez Nazaret, Redondo Juan Miguel, Duarte Juan
Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Front Physiol. 2020 Apr 16;11:277. doi: 10.3389/fphys.2020.00277. eCollection 2020.
Short-chain fatty acids (SCFAs) are among the main classes of bacterial metabolic products and are mainly synthesized in the colon through bacterial fermentation. Short-chain fatty acids, such as acetate, butyrate, and propionate, reduce endothelial activation induced by proinflammatory mediators, at least in part, by activation of G protein-coupled receptors (GPRs): GPR41 and GPR43. The objective of the 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 nicotinamide adenine dinucleotide phosphate oxidase system and the mitochondria; diminishes vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser; reduces GPR41 and GPR43 mRNA level; and reduces the endothelium-dependent relaxant response to acetylcholine in aorta. Coincubation with butyrate and acetate, but not with propionate, increases both NO production and pSer-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 affects 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.
短链脂肪酸（SCFAs）是细菌代谢产物的主要类别之一，主要通过细菌发酵在结肠中合成。乙酸、丁酸和丙酸等短链脂肪酸至少部分通过激活G蛋白偶联受体（GPRs）：GPR41和GPR43，来减少促炎介质诱导的内皮细胞活化。本研究的目的是分析短链脂肪酸对血管紧张素II（AngII）诱导的内皮功能障碍可能的保护作用。在存在或不存在短链脂肪酸（5 - 10 mM）的情况下，将大鼠主动脉内皮细胞（RAECs）和大鼠主动脉与AngII（1 μM）孵育6小时。在RAECs中，我们发现AngII可降低钙离子载体A23187刺激的一氧化氮（NO）生成；增加烟酰胺腺嘌呤二核苷酸磷酸氧化酶系统和线粒体产生的活性氧（ROS）；减少丝氨酸处血管舒张刺激磷蛋白（VASP）的磷酸化；降低GPR41和GPR43 mRNA水平；并降低主动脉对乙酰胆碱的内皮依赖性舒张反应。与丁酸和乙酸共同孵育，但不与丙酸共同孵育，可增加NO生成和pSer - VASP，降低细胞内ROS浓度，并改善对乙酰胆碱的舒张反应。GPR41受体拮抗剂β - 羟基丁酸和GPR43受体拮抗剂GLPG0794可抑制丁酸的有益作用。丁酸可抑制AngII诱导的GPR41和GPR43的下调，而乙酸和丙酸则无此作用。β - 羟基丁酸和GLPG0794均不影响乙酸对内皮功能障碍的保护作用。总之，乙酸和丁酸通过增加NO的生物利用度来改善AngII诱导的内皮功能障碍。丁酸的作用似乎与GPR41/43激活有关，而乙酸的作用则独立于GPR41/43。
