Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Abstract

Branched‐chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro‐inflammatory responses through the transcription factor NF‐κB that resulted in the release of intracellular adhesion molecule‐1 and E‐selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA‐induced pro‐oxidant and pro‐inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre‐contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels.

Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension

“…www.nature.com/scientificreports www.nature.com/scientificreports/ signature found in women could be at least partially linked to this difference in BMI. Elevated concentrations of branched amino acids are known to promote endothelial dysfunction, inflammation, and oxidative stress 57 and may promote hypertension 58 . Insulin resistance could contribute to hypertension through altered NO release 59 .…”

Iridoid Glycosides From Morinda Officinalis F. C. How Alleviate Rheumatoid Arthritis and Its Associated Bone Deterioration and Protect Against Methotrexate-induced Toxicity in Collagen-induced Arthritic Rats

“…Furthermore, taurine, which has anti-oxidant properties, can down-regulate the production of pro-in ammatory cytokines such as TNF-α, and also protect OBs against oxidative damage via Wnt/β-catenin-mediated activation of the extracellular regulated protein kinase (ERK) signaling pathway [37]. Additionally, elevation of branched-chain amino acids (BCAA: leucine, isoleucine and valine) can cause in ammation and oxidative stress in endothelial cells, thereby facilitating in ammatory cell adhesion and endothelial dysfunction [38]. On the other hand, metabolism of some amino acids can also regulate bone metabolism.…”

Metabonomic study of the protective effect of Fukeqianjin formula on multi-pathogen induced pelvic inflammatory disease in rats

“…Amino acids are not only essential substances of proteins, but also as signal molecules regulate various physiological functions of the organism, such as precursors of many neurotransmitters and hormones, and intermediates of TCA circulation and glyconeogenesis [ 59 ]. Previous reports have demonstrated that branched-chain amino acids can increase the expression of eNOS and nitrotyrosine, and induce inflammatory response by activating the transcription factor NF-κB in endothelial cells [ 60 ]. Four potential biomarkers related to amino acid metabolism, including l -alanine, Ser-Lys-Lys-Ile, diaminomethylidene- l -ornithine, and Arg-Met-Arg-Thr, have been shown in Table 1 .…”