Biochemical and Biophysical Research Communications, Vol.530, No.1, 95-99, 2020
Trimethylamine N-oxide impairs perfusion recovery after hindlimb ischemia
Background: The circulating level of trimethylamine N-oxide (TMAO) has been reported to be associated with the prognosis of of peripheral arterial disease (PAD) patients. However, the effects of TMAO on neovascularization and perfusion recovery after PAD are not known. Methods: Unilateral hindlimb ischemia was generated in mice as experimental PAD model, TMAO or 3,3-dimethyl-1-butanol (DMB) were added to the drinking water for these mice. In cultured endothelial cells, TMAO was added to culture medium to assess the effects on cell viability and tube formation under simulated ischemic conditions. Results: In experimental PAD, TMAO treatment increased malondialdehyde (MDA), interleukin (IL)-1 beta and IL-6 in the ischemic muscle, impaired perfusion recovery, and decreased capillary density. On the other hand, mice fed with DMB drinking water showed lower TMAO level, interleukin (IL)-1 beta and IL-6, and higher vascular endothelial growth factor in the ischemic muscle, and better perfusion recovery after experimental PAD. In cultured endothelial cell, TMAO decreased intracellular nitric oxide, cell viability and tube formation, and increased intracellular reactive oxygen species levels. Conclusions: TMAO increases oxidative stress and inflammation, and impairs perfusion recovery and angiogenesis in experimental PAD. (C) 2020 Elsevier Inc. All rights reserved.