Aims/hypothesis Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications.
Methods GKT137831 was administered at two doses, 30 mg kg(-1) day(-1) and 60 mg kg(-1) day(-1), to ApoE (-/-) mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks.
Result Consistent with Nox4 (-/-) mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg(-1) day(-1) and 60 mg kg(-1) day(-1) doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where Nox1 (-/y) and Nox4 (-/-) mice have yielded qualitatively opposing results, the net effect of pharmacological NOX1/4 inhibition was protection, albeit to a lower extent and only at the lower 30 mg kg(-1) day(-1) dose.
Conclusion/interpretation As dose-dependent and tissue-specific effects of the dual NOX1/4 inhibitor GKT137831 were observed, it is critical to define in further studies the relative balance of inhibiting NOX4 vs NOX1 in the micro- and macrovasculature in diabetes.
- NADPH oxidase
- Oxidative stress
- DIABETES-ASSOCIATED ATHEROSCLEROSIS
- NADPH OXIDASE
- ACCELERATED ATHEROSCLEROSIS
- PHARMACOLOGICAL INHIBITION
- OXIDATIVE STRESS
- KNOCKOUT MICE
- MOUSE MODEL
- KEY ROLE