Abstract P062: Trimethylamine N-oxide Impairs Endothelium-dependent Relaxation In Aorta Of Non-diabetic And Diabetic Mice

Abstract

Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite related with cardiovascular diseases. Circulating levels of TMAO are increased in diabetes and TMAO is associated with the development of insulin resistance. We aimed to investigate if TMAO impairs vascular reactivity in diabetes. The aorta of 16-week old male diabetic (db/db) and db/+ mice were mounted in a myograph and concentration-response curves to acetylcholine (ACh; 1 nM - 10 μM), sodium nitroprusside (SNP; 0.1 nM - 1 μM) and phenylephrine (PE; 1 nM - 10 μM) were obtained in the presence of TMAO (100 mM, 30 min), repeated in the presence of the antioxidant tempol (10 μM), the NLRP3 inhibitor (MCC950, 1 μM) or IL-1β receptor antagonist (IL1RA, 20 ng/mL). TMAO did not affect the contraction of PE or relaxation to SNP in aorta of db/db or db/+ mice, but decreased the potency of ACh in the aorta of db/+ (pEC 50 : 7.96 + 0.22 vs 7.25 + 0.16, lean or TMAO, respectively) and db/db (pEC 50 : 7.91 + 0.10 vs 7.17 + 0.09, db/db vs TMAO, respectively). In db/+ mice, tempol improved the potency of ACh (pEC 50 - TMAO: 7.05 + 0.21 vs TMAO + tempol 7.42 + 0.15) while further impairment in the relaxation to ACh was seen in the presence of MCC950 or IL1RA. In conclusion, TMAO impairs endothelium-dependent relaxation of aorta through the production of reactive oxygen species.