Abstract
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 Ser239; 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 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 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.
Highlights
Vascular endothelial cells are critically involved in cardiovascular homeostasis by controlling thrombotic, inflammatory, and atherogenic states within vascular wall (Thomas et al, 2008)
We found that concentrations of butyrate ≥100 μM and acetate ≥1 mM were able to prevent the reduction in nitric oxide (NO) production induced by Angiotensin II (AngII) (Supplementary Figure S1)
When we analyzed eNOS phosphorylation at the active site Ser1177, we found that AngII was unable to reduce significantly the ratio peNOSSer1177/eNOS as compared the control, and the presence of butyrate did not modify the level of phosphorylation (Supplementary Figure S2B)
Summary
Vascular endothelial cells are critically involved in cardiovascular homeostasis by controlling thrombotic, inflammatory, and atherogenic states within vascular wall (Thomas et al, 2008). Endothelial dysfunction, defined as a loss of endothelium to induce vasodilatation, is an earliest indicator of development of cardiovascular disease and appears in the onset and during the progression of hypertension, atherosclerosis, cardiac ischemia, or stroke (Versari et al, 2009; Dharmashankar and Widlansky, 2010; Gkaliagkousi et al, 2015; Vasquez et al, 2019). Angiotensin II (AngII) is the major effector peptide of renin–angiotensin system. This peptide is a strong stimulus for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the main source of ROS in the vascular wall, which induces vascular oxidative stress and endothelial dysfunction (Virdis et al, 2011). Chronic exposure to AngII induces hypertension and vascular remodeling associated to an increased production of NADPH oxidase-derived ROS (Cifuentes et al, 2000)
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