PPAR-αAgonist Fenofibrate Upregulates Tetrahydrobiopterin Level through Increasing the Expression of Guanosine 5′-Triphosphate Cyclohydrolase-I in Human Umbilical Vein Endothelial Cells

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. Guanosine 5′-triphosphate cyclohydrolase-I (GTPCH-I) is a key limiting enzyme for BH4 synthesis. In the present in vitro study, we investigated whether peroxisome proliferator-activated receptor α (PPAR-α) agonist fenofibrate could recouple eNOS by reversing low-expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms. After human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) for 24 hours, the levels of cellular eNOS, BH4 and cell supernatant NO were significantly reduced compared to control group. And the fluorescence intensity of intracellular ROS was significantly increased. But pretreated with fenofibrate (10 umol/L) for 2 hours before cells were induced by LPS, the levels of eNOS, NO, and BH4 were significantly raised compared to LPS treatment alone. ROS production was markedly reduced in fenofibrate group than LPS group. In addition, our results showed that the level of intracellular GTPCH-I detected by western blot was increased in a concentration-dependent manner after being treated with fenofibrate. These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH-I.

Fenofibrate Improves Vascular Endothelial Function by Reducing Oxidative Stress While Increasing Endothelial Nitric Oxide Synthase in Healthy Normolipidemic Older Adults

“…21 In the present study, we report for the first time that endothelial cell eNOS protein is increased in humans with fenofibrate treatment. This finding is consistent with previous data showing that fenofibrate increases eNOS protein expression in cultured endothelial cells 8, 22 and the aorta of rodents. 9 In contrast, eNOS protein expression was reported not to change and NO was reported not contribute to the improvements in dilation in response to acetylcholinein the small mesenteric arteries of old rats with fenofibrate treatment.…”

“…6 It is possible that fenofibrate may influence eNOS and the NO contribution to acetylcholine-induced dilation of small resistance arteries differently than in conduit arteries of humans in response to flow (present study), or in aorta or cell culture. 8, 22 We were unable to measure the NO contribution to dilation using the brachial FMD model, and thus cannot determine if the increased eNOS expression with fenofibrate had functional benefit.…”

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

“…Another study suggested that metformin improved endothelial function by suppressing 26s proteasome-mediated GTPCH1 degradation to increase the level of BH4 (36). Furthermore, we reported previously that PPAR␣ agonist fenofibrate upregulated BH4 level by increasing the expression of GTPCH1 in HUVECs (26). Our results suggested that exendin-4 increased the level of GTPCH1 in a dose-and timedependent manner and thus might lead to improvement of the …”

“…The umbilical cord samples were collected and washed three times with phosphate-buffered saline (PBS). Endothelial cells were isolated by collagenase digestion and cultured in Medium 199 (Hyclone, Logan, UT) supplemented with 10% fetal bovine serum (FBS), as described previously (26). The cells of five to six passages were used in all experiments, which were examined to ensure specific characteristics of endothelial cells by cytochemical staining.…”

Arsenic, Reactive Oxygen, and Endothelial Dysfunction

“…•2 content (Okayasu et al, 2008;Potenza et al, 2009;Antoniades et al, 2011;Liu et al, 2011a). Time-and concentration-dependent effects are also apparent after exposure of rats to environmentally relevant low-tomoderate As III levels in drinking water [20 mg/l; with 10 mg/l deemed as the safe level by the World Health Organization (http://www.who.int/water_sanitation_health/publications/2011/ dwq_guidelines/en/)], where acetylcholine-induced aortic relaxation is maintained after 2 months but reduced after 7 months' exposure (Cifuentes et al, 2009).…”