DPP-4 Inhibitors: Preservation of Endothelial Function in the Presence of Oxidative Stress

Aims: A major cause of morbidity in diabetes is dysfunction of the vasculature by impairment of endothelial function. There is evidence that the dipeptidyl peptidase 4 (DPP-4) inhibitors may, in addition to lowering blood glucose, have beneficial effects on endothelial function, perhaps through antioxidant activity. We investigated the ability of the DPP-4 inhibitor linagliptin to preserve endothelial function in the presence of diabetes-induced oxidative stress.
Method: We examined the effect of linagliptin on endothelium-dependent relaxation in mesenteric arteries and aortae from rats with streptozotocin (STZ)-induced type 1 diabetes or hyperglycaemic db/db mice respectively. Vascular superoxide production was measured and eNOS and NADPH oxidase 2 (Nox2) were measured by western blotting.
Results: Vascular superoxide generation was elevated in STZ treated rats and in db/db mice which was accompanied by an increased vascular Nox2 and uncoupling of endothelial nitric oxide synthase (eNOS) indicated by a decreased expression of the enzyme as a dimer. Endothelium-dependent relaxation in response to acetylcholine (ACh) was significantly impaired in these models of diabetes. Linagliptin treatment of the rats (2 mg/kg po daily for 4 weeks) or mice (3 mg/kg po daily for 6 weeks) did not affect the elevated glucose levels observed in either rats or mice but significantly reduced vascular superoxide production. Linagliptin significantly increased the maximum response to ACh in both rat and mouse arteries.
Conclusions: The DPP-4 inhibitor linagliptin can reduce oxidative stress and improve endothelium-dependent relaxation without preventing hyperglycaemia in rodent models of type 1 and type 2 diabetes.
Key words: Diabetes, DPP-4 inhibitor, endothelium, oxidative stress