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.
| Original language | English |
|---|---|
| Pages (from-to) | 927-937 |
| Number of pages | 11 |
| Journal | Diabetologia |
| Volume | 60 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2017 |
Keywords
- Atherosclerosis
- Diabetes
- NADPH oxidase
- Nephropathy
- Oxidative stress
Cite this
}
Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease. / Gray, Stephen P.; Jha, Jay C.; Kennedy, Kit; Bommel, Erik van; Chew, Phyllis; Szyndralewiez, Cedric; Touyz, Rhian M.; Schmidt, Harald H. H. W.; Cooper, Mark E.; Jandeleit-Dahm, Karin A. M.
In: Diabetologia, Vol. 60, No. 5, 05.2017, p. 927-937.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
AU - Gray, Stephen P.
AU - Jha, Jay C.
AU - Kennedy, Kit
AU - Bommel, Erik van
AU - Chew, Phyllis
AU - Szyndralewiez, Cedric
AU - Touyz, Rhian M.
AU - Schmidt, Harald H. H. W.
AU - Cooper, Mark E.
AU - Jandeleit-Dahm, Karin A. M.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Diabetes
KW - NADPH oxidase
KW - Nephropathy
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85011551497&partnerID=8YFLogxK
U2 - 10.1007/s00125-017-4215-5
DO - 10.1007/s00125-017-4215-5
M3 - Article
VL - 60
SP - 927
EP - 937
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 5
ER -