The Novel Role of Fenofibrate in Preventing Nicotine- and Sodium Arsenite-Induced Vascular Endothelial Dysfunction in the Rat

Abstract

The present study investigated the effect of fenofibrate, an agonist of PPAR-alpha, in nicotine- and sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) and sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) were administered to produce VED in rats. The scanning electron microscopy study in thoracic aorta revealed that administration of nicotine or sodium arsenite impaired the integrity of vascular endothelium. Further, administration of nicotine or sodium arsenite significantly decreased serum and aortic concentrations of nitrite/nitrate and subsequently reduced acetylcholine-induced endothelium-dependent relaxation. Moreover, nicotine or sodium arsenite produced oxidative stress by increasing serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide generation. However, treatment with fenofibrate (30 mg/kg/day, p.o.) or atorvastatin (30 mg/kg/day p.o., a standard agent) significantly prevented nicotine- and sodium arsenite-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentrations of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium-dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Conversely, co-administration of L-NAME (25 mg/kg/day, i.p.), an inhibitor of nitric oxide synthase, markedly attenuated these vascular protective effects of fenofibrate. The administration of nicotine or sodium arsenite altered the lipid profile by increasing serum cholesterol and triglycerides and consequently decreasing high-density lipoprotein levels, which were significantly prevented by treatment with fenofibrate or atorvastatin. It may be concluded that fenofibrate improves the integrity and function of vascular endothelium, and the vascular protecting potential of fenofibrate in preventing the development of nicotine- and sodium arsenite-induced VED may be attributed to its additional properties (other than lipid lowering effect) such as activation of eNOS and generation of NO and consequent reduction in oxidative stress.

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy

“…On the other hand, treatment with fenofibrate significantly ameliorated the impaired renal oxidative status which is accompanied with increases in the renal levels of NO and eNOS mRNA, suggesting the renoprotective effect of fenofibrate is possibly via reversed eNOS uncoupling and improvement of endothelial function. Our results are consistent with previous studies [50,51] which reported that fenofibrate improves the integrity and function of vascular endothelium through the activation/upregulation of eNOS expression and generation of NO with a reduction in oxidative stress [50]. Previously, it has been shown that the AMPK pathway reduces intracellular ROS levels [19].…”

Arsenic, Reactive Oxygen, and Endothelial Dysfunction

“…Consistent with this proposal, more prolonged exposure of rats to As III (1.5 mg/kg per day for 2 weeks) attenuates ex vivo aortic relaxations to acetylcholine in association with elevated serum markers of oxidative stress (Kaur et al, 2010). Indeed, in this particular experimental model of arsenic toxicity, serum oxidant markers and impaired vessel relaxation (see Fig.…”

“…Indeed, in this particular experimental model of arsenic toxicity, serum oxidant markers and impaired vessel relaxation (see Fig. 2) are restored by the peroxisome proliferator-activated receptor g ligands fenofibrate and roziglitazone and also by atorvastatin (Jindal et al, 2008;Kaur et al, 2010;Verma et al, 2010), agents that are associated variously with increased (6R)-5,6,7,8-tetrahydrobiopterin synthesis (through the upregulation of GTP-cyclohydrolase-I), reduced serum levels of asymmetric dimethylarginine (an endogenous NOS inhibitor), increased eNOS phosphorylation, and suppressed vascular p22 phox expression, nitrotyrosine formation, and O 2…”

Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha

“…(53) The induction of 2 oxidative stress markers by TNF-alpha in the CMECs (p22PHOX and mitochondrial ROS levels) was prevented by fenofibrate pretreatment. Fenofibrate's antioxidant properties have previously been demonstrated in an in vivo study by reducing superoxide anion levels and p22PHOX expression in a model of nicotine-treated rat aortic tissue; (54,55) however the authors did not investigate the effects in endothelial cells. Although fenofibrate pretreatment did not alter TNF-alpha-induced activation of NF-KB in our hands, it was associated with a marked improvement in cell viability and reduced caspase-3 mediated apoptosis.…”