Combined Nox1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

Gray, S. P., Jha, J. C., Kennedy, K., Van Bommel, E., Chew, P., Szyndralewiez, C., Touyz, R. M. , Schmidt, H. H.H.W., Cooper, M. E. and Jandeleit-Dahm, K. A.M. (2017) Combined Nox1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease. Diabetologia, 60(5), pp. 927-937. (doi: 10.1007/s00125-017-4215-5) (PMID:28160092)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Touyz, Professor Rhian
Authors: Gray, S. P., Jha, J. C., Kennedy, K., Van Bommel, E., Chew, P., Szyndralewiez, C., Touyz, R. M., Schmidt, H. H.H.W., Cooper, M. E., and Jandeleit-Dahm, K. A.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetologia
Publisher:Springer
ISSN:0012-186X
ISSN (Online):1432-0428
Published Online:03 February 2017

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