Tranilast Alleviates Endothelial Dysfunctions and Insulin Resistance via Preserving Glutathione Peroxidase 1 in Rats Fed a High-Fat Emulsion

Abstract

Abstract. We investigated the effects of treatment with tranilast on vascular and metabolic dysfunction induced by a high-fat emulsion intragastric administration. Wistar rats were randomized to receive water or high-fat emulsion with or without tranilast treatment (400 mg/kg per day) for 4 weeks. Insulin sensitivity was determined with a hyperinsulinemic-euglycemic clamp experiment and short insulin tolerance test. Vascular reactivity was evaluated using aortic rings in organ chambers. Glutathione peroxidase 1 (GPX1) expressions, eNOS phosphorylation and activity, MCP-1, H 2 O 2 formation, and NO production were determined in vascular or soleus tissues. Tranilast treatment was found to prevent alterations in vascular reactivity and insulin sensitivity and to prevent increases in plasma glucose and insulin noted in the high-fat emulsion-treated rats. These were associated with increased antioxidant enzyme GPX1 expression, eNOS phosphorylation and activity, and NO production, but reductions in H 2 O 2 accumulation. Moreover, tranilast preserved GPX1 expression in palmitic acid (PA)-treated endothelial cells with a consequent decreased ROS formation and increased eNOS phosphorylation and NO production. Therefore, oxidative stress induced by a relatively short-term high-fat diet could cause the early development of vascular and metabolic abnormalities in rats, and tranilast has a beneficial effect in vascular dysfunctions and insulin resistance via preserving GPX1 and alleviating oxidative stress.

Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

“…We observed that, after preincubation with this drug, ACh-induced relaxation was decreased to a similar extent in both experimental conditions indicating that NO does not participate in the effect observed after preincubation with tranilast. This was confirmed by the fact that NO release, superoxide anion formation and vasodilator response to NO donor DEA-NO were not modified after preincubation with tranilast, similarly to reported in rat aorta [15]. All these results contrast with our previous results in superior mesenteric artery, where we observed decreases in neuronal NO and superoxide anion releases and an increase in the vasodilator response to DEA-NO after tranilast preincubation [14].…”

Tranilast: A review of its therapeutic applications

“…Tranilast treatment (400 mg/kg per day for 4 weeks) prevented vascular dysfunction, insulin resistance, as well as increases in plasma glucose in highfat emulsion-treated rats. These effects were linked with preserving antioxidant enzyme GPX1 expression, eNOS activity and NO production, but reductions in H 2 O 2 accumulation alleviated oxidative damage and inflammation accordingly [151]. In addition, treatment with tranilast enhanced glucose uptake in pancreatic beta-cells and islets [152].…”

“…Tranilast was found to prevent the reduction in eNOS phosphorylation and activity, along with NO production, in the vascular tissues [151]. Nitric oxide synthase (iNOS) mRNA and protein expression, as well as the release of NO from N9 microglial cells, are inhibited when cells are exposed to tranilast [180].…”

Pathogenesis of Chronic Hyperglycemia: From Reductive Stress to Oxidative Stress

“…As ROS production is a common feature of the above described pathways [119, 164], chronic oxidative stress certainly plays a central role in the development of diabetes and diabetic complications [22, 165, 166]. Indeed, it has been reported that ROS can induce insulin resistance [74, 167], impair insulin synthesis [168], and impair beta cell insulin secretion [97, 169]. Additionally, oxidative stress biomarkers have been shown to be increased in individuals who exhibit insulin resistance [170–173] or insulin secretion impairment [174–177], indicating a positive correlation between oxidative stress and insulin resistance and insulin secretion impairment.…”