Tocomin Restores Endothelium-Dependent Relaxation in the Diabetic Rat Aorta by Increasing NO Bioavailability and Improving the Expression of eNOS.

Saher F Ali,Owen L Woodman

doi:10.3389/fphys.2019.00186

Abstract

We aimed to determine whether tocomin, an extract from palm oil that has a high tocotrienol content, was able to prevent diabetes-induced endothelial dysfunction. To induce type 1 diabetes streptozotocin (50 mg/kg) was injected into the tail vein of Wistar rats. Six weeks later the diabetic rats, and normal rats injected with citrate buffer, commenced treatment with tocomin (40 mg/kg/day sc) or its vehicle (peanut oil) for a further 4 weeks. Aortae isolated from diabetic rats had impaired acetylcholine (ACh)-induced endothelium-dependent relaxation compared to normal rat aortae but there was no change in endothelium-independent relaxation in response to sodium nitroprusside. By contrast, responses to ACh in aortae from diabetic rats treated with tocomin were not different to normal rats. In addition to impaired endothelium-dependent relaxation the diabetic aortae had increased expression of the NADPH oxidase Nox2 subunit, increased generation of superoxide and decreased expression of eNOS and all of these effects were prevented by tocomin treatment. Tocomin did not affect plasma glucose levels. The impaired response to ACh in vitro was maintained in the presence of TRAM-34 and apamin, selective inhibitors of calcium-activated potassium (KCa) channels, indicating diabetes impaired the contribution of NO to endothelium-dependent relaxation. By contrast, neither diabetes nor tocomin treatment influenced EDH-type relaxation as, in the presence of L-NNA, an inhibitor of eNOS, and ODQ, to inhibit soluble guanylate cyclase, responses to ACh were similar in all treatment groups. Thus tocomin treatment improves NO mediated endothelium dependent relaxation in aortae from diabetic rats associated with a decrease in vascular oxidant stress but without affecting hyperglycaemia.

Highlights

Diabetes is commonly associated with vascular dysfunction, an impairment of endothelium-dependent relaxation, which is regarded as critical to the development of diabetes-induced vascular complications (De Vriese et al, 2000)
Nox2- induced superoxide production was significantly elevated in diabetic rat aortae in comparison to the normal rat aorta
We did not test a possible role for prostanoids in the current study we previously found that the cyclooxygenase inhibitor indomethacin had no effect on endothelium-dependent relaxation of aortae from normal or diabetic rats (Joshi and Woodman, 2012)

Summary

Introduction

Diabetes is commonly associated with vascular dysfunction, an impairment of endothelium-dependent relaxation, which is regarded as critical to the development of diabetes-induced vascular complications (De Vriese et al, 2000). Tocomin Improves Endothelial Function in Diabetes of vascular complications (Giacco and Brownlee, 2010; Fiorentino et al, 2013; Hammes, 2018). This is mainly due to free radicals damaging the vascular endothelium which produces the potent vasorelaxant nitric oxide (NO) (Treuer and Gonzalez, 2015). There is a search for effective antioxidants that might prevent diabetes induced vascular dysfunction and its subsequent cardiovascular complications. There has been considerable interest in the antioxidant activity and in the potential use of vitamin E to reduce cardiovascular disease and its complications (Mathur et al, 2015; Schmidt et al, 2015). There is emerging evidence that tocotrienols, which are structurally related to the tocopherols may possess superior antioxidant activity (Serbinova et al, 1991; Serbinova and Packer, 1994; Atkinson et al, 2008) and may have distinct biological activities (Khanna et al, 2005; Sen et al, 2008; Aggarwal et al, 2010)

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