Abstract
Seleno-organic glutathione peroxidase (GPx) mimetics, including ebselen (Eb), have been tested in in vitro studies for their ability to scavenge reactive oxygen and nitrogen species, including hydrogen peroxide and peroxynitrite. In this study, we investigated the efficacies of two Eb analogues, m-hydroxy ebselen (ME) and ethanol-ebselen (EtE) and compared these with Eb in cell based assays. We found that ME is superior in attenuating the activation of hydrogen peroxide-induced pro-inflammatory mediators, ERK and P38 in human aortic endothelial cells. Consequently, we investigated the effects of ME in an in vivo model of diabetes, the ApoE/GPx1 double knockout (dKO) mouse. We found that ME attenuates plaque formation in the aorta and lesion deposition within the aortic sinus of diabetic dKO mice. Oxidative stress as assessed by 8-OHdG in urine and nitrotyrosine immunostaining in the aortic sinus and kidney tubules, was reduced by ME in diabetic dKO mice. ME also attenuated diabetes-associated renal injury which included tubulointerstitial fibrosis and glomerulosclerosis. Furthermore, the bioactivity of the pro-fibrotic cytokine transforming growth factor-β (TGF-β) as assessed by phospho-Smad2/3 immunostaining was attenuated after treatment with ME. TGF-β-stimulated increases in collagen I and IV gene expression and protein levels were attenuated by ME in rat kidney tubular cells. However, in contrast to the superior activity of ME in in vitro and cell based assays, ME did not further augment the attenuation of diabetes-associated atherosclerosis and renal injury in our in vivo model when compared with Eb. In conclusion, this study strengthens the notion that bolstering GPx-like activity using synthetic mimetics may be a useful therapeutic strategy in lessening the burden of diabetic complications. However, these studies highlight the importance of in vivo analyses to test the efficacies of novel Eb analogues, as in vitro and cell based assays are only partly predictive of the in vivo situation.
Highlights
Oxidative stress is recognised as playing a major role in the pathophysiology of disease, with evidence for its contribution to processes such as inflammation, fibrosis, and atherosclerotic lesion formation [1]
Our results have shown that the modified Eb analogue, m-hydroxy ebselen (ME), attenuates oxidative stress, atherosclerosis and the hallmarks of diabetic nephropathy in the diabetic ApoE/GPx1 double knockout (dKO) mouse
We had previously extensively characterised a diverse range of glutathione peroxidase (GPx) mimetics using computational, physicochemical and biochemical methods [23,33]
Summary
Oxidative stress is recognised as playing a major role in the pathophysiology of disease, with evidence for its contribution to processes such as inflammation, fibrosis, and atherosclerotic lesion formation [1]. The two-electron reactive oxygen and nitrogen species (RO/NS) such as hydrogen peroxide and peroxynitrite (PN, ONOO2) are considered more damaging than oneelectron radicals, with greater disease-mediating capabilities [2]. Given the injurious nature of these two-electron reactive species, attention has focused on antioxidants to lower the concentration of these RO/NS to avert disease. Recent interest has turned to the benefits of bolstering endogenous antioxidant-like defences, in particular that of the naturally occurring glutathione peroxidase (GPx) enzymes, since these antioxidants efficiently remove two-electron reactive species such as hydrogen and lipid peroxides as well as peroxynitrites [12]. The development of small synthetic compounds that mimic the activities of the GPx enzymes have received considerable attention for their potential to lessen prevailing RO/NS and thereby reverse or avert disease [13,14]
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