Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

  • Diabetologia. 2017 May;60(5):927-937. doi: 10.1007/s00125-017-4215-5.
Stephen P Gray  1  2 ,  Jay C Jha  3 ,  Kit Kennedy  3 ,  Erik van Bommel  3 ,  Phyllis Chew  3 ,  Cedric Szyndralewiez  4 ,  Rhian M Touyz  5 ,  Harald H H W Schmidt  6  7 ,  Mark E Cooper  3  8 ,  Karin A M Jandeleit-Dahm  3  8
Affiliations
  • 1. Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. [email protected].
  • 2. Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia. [email protected].
  • 3. Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
  • 4. Genkyotex SA, Geneva, Switzerland.
  • 5. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
  • 6. Department of Pharmacology, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
  • 7. Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
  • 8. Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.
PMID: 28160092 DOI: 10.1007/s00125-017-4215-5
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.

Keywords
Atherosclerosis; Diabetes; NADPH oxidase; Nephropathy; Oxidative stress.