Protective effects of kaempferol against endothelial damage by an improvement in nitric oxide production and a decrease in asymmetric dimethylarginine level

Previous investigations have shown that asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS) and that ADMA is a risk factor for endothelial dysfunction. The objective of this study was to investigate the protective effect of kaempferol, a naturally occurring flavonoid antioxidant agent, against endothelial damage and the mechanisms involved. The experiments were performed in aorta and plasma from C57BL/6J control and apolipoprotein E-deficient (ApoE−/−) mice treated or not with kaempferol (50 or 100 mg/kg, intragastrically) for 4 weeks, and in human umbilical vein endothelial cells (HUVECs) pretreated or not with kaempferol (1, 3 or 10 µM) for 1 h and exposed to lysophosphatidylcholine (LPC) (10 µg/mL) for 24 h. Kaempferol treatment improved endothelium-dependent vasorelaxation, increased the maximal relaxation value, and decreased the half-maximum effective concentration concomitantly with an increase in nitric oxide plasma concentration, a decrease in ADMA and malondialdehyde (MDA) plasma concentrations, and increase in the expression of aortic endothelial NOS (eNOS) as well as dimethylarginine dimethylaminohydrolase II (DDAH II) in ApoE−/− mice. In addition, LPC caused a reduction in NO production, an increase in ADMA concentration concomitantly with a decreased expression of eNOS and DDAH II in HUVECs, and the effect of LPC was abolished by kaempferol. Treatment with kaempferol also significantly decreased reactive oxygen species production in mice aorta and in HUVECs. The present results suggest that the protective effect of kaempferol against endothelial damage may be associated with an improvement in NO production and a decrease in ADMA level.