Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

Abstract

Background/Aims: Elevated production of reactive oxygen species (ROS) is linked to endothelial dysfunction and is one of the key contributors to the pathogenesis of diabetic vascular complications. Emerging evidence has indicated that ellagic acid (EA), a polyphenol found in fruits and nuts, possesses numerous biological activities including radical scavenging. However, whether EA exerts a vasculo-protective effect via antioxidant mechanisms in blood vessels exposed to diabetic conditions remains unknown. Accordingly, the goal of this current study was to determine whether EA decreases vascular ROS production and thus ameliorates endothelial dysfunction in the diabetic milieu. Methods: Intact rat aortas and human aortic endothelial cells (HAEC) were stimulated with 30mM high glucose (HG) with and without EA co-treatment. Endothelium-dependent vasodilation was measured using a wire myograph. Gene and protein expression of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 4 (NOX4) were detected using RT-PCR and western blotting, respectively. Oxidative stress was determined by measuring ROS levels using dihydroethidium (DHE) staining. Results: Intact aortas exposed to HG condition displayed exacerbated ROS production and impairment of endothelium-dependent vasodilation, characterizing endothelial dysfunction. These effects were markedly reduced with EA treatment. HG enhanced ROS production in HAEC, paralleled by increased ERK1/2 activation and NOX4 expression. EA treatment blunted the increase of ROS generation, ERK1/2 activation and decreased NOX4. Conclusions: EA significantly decreases endothelial ROS levels and ameliorates the impairment of vascular relaxation induced by HG. Our results suggest that EA exerts a vasculo-protective effect under diabetic conditions via an antioxidant effect that involves inhibition of ERK1/2 and downregulation of NOX4.

Fibrinopeptide A Induces Expression of C-Reactive Protein via the ROS-ERK1/2/ P38-NF-κB Signal Pathway in Vascular Smooth Muscle Cells

“…ROS are both the important second messenger and the direct participant of oxidative stress [36]. Low concentration of ROS is permanently produced in cells, which plays a role as signal molecules.…”

Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats

“…Oxidative stress was determined in frozen and unfixed liver tissue sections by measuring levels of superoxide anion utilizing the fluorescent probe Dihydroethidium (DHE), as previously described [ 18 ]. Briefly, cryosections of livers from both groups (GK and GK + EA) were incubated with 25 µM DHE in a light-protected humidified chamber at 37 °C for 30 min and washed with PBS.…”

“…Ellagic acid (2,3,7,8-tetrahydroxy-chromeno [5,4,3-cde] chromene-5, 10-dione) (EA) is a natural polyphenolic compound that is commonly found in fruits, such as raspberries, pomegranates, grapes and blackcurrants as well as in nuts. Our group has recently shown that EA improves vascular function in blood vessels exposed to hyperglycemic conditions through the reduction of oxidative stress [ 18 ]. In rodent models of hepatic ischemia reperfusion and aging, EA has been demonstrated to have beneficial effects on the liver by decreasing oxidative stress [ 19 , 20 ].…”

Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats

“…32 Briefly, cardiomyocytes were loaded with DHE at a concentration of 10 μmol/L for 30 minutes at 37°C. 32 Briefly, cardiomyocytes were loaded with DHE at a concentration of 10 μmol/L for 30 minutes at 37°C.…”

“…Superoxide generation in cultured cardiomyocytes was estimated by DHE staining as previously described. 32 Briefly, cardiomyocytes were loaded with DHE at a concentration of 10 μmol/L for 30 minutes at 37°C. The DHE fluorescence of DHE-labelled positive nuclei was calculated in each of five randomly selected fields and was expressed as a percentage of the DHE-stained positive myocyte nuclei compared with control by a quantitative morphometric method.…”