Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease.
Diabetologia
; 60(5): 927-937, 2017 05.
Article
en En
| MEDLINE
| ID: mdl-28160092
ABSTRACT
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.RESULTS:
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. CONCLUSIONS/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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Piridinas
/
NADPH Oxidasas
/
Complicaciones de la Diabetes
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Diabetes Mellitus Experimental
/
NADH NADPH Oxidorreductasas
Tipo de estudio:
Guideline
Límite:
Animals
Idioma:
En
Revista:
Diabetologia
Año:
2017
Tipo del documento:
Article
País de afiliación:
Australia