Saxagliptin prevents vascular remodeling and oxidative stress in db/db mice. Role of endothelial nitric oxide synthase uncoupling and cyclooxygenase

To explore the hypothesis that DPP-IV are involved in the diabetes-induced vascular damage, we assessed the vascular effects of chronic administration of saxagliptin (Saxa) or metformin (Met) in db/db mice, a model of type 2 diabetes, evaluating vascular structure and endothelial function in mesenteric small arteries. The increases in media/lumen and media cross sectional area were prevented by Saxa. In db/db, the blunted response to acetylcholine was only marginally affected by L-NAME (NO-synthase inhibitor), improved by SC-560 (cyclooxygenase-1 inhibitor) or SQ-29548 (thromboxane receptor antagonist), and totally restored by Apocynin (NAD(P)H-oxidase inhibitor). DFU (cyclooxygenase-2 inhibitor) had no effect. Saxa improved acetylcholine-induced relaxation, which returned partially sensitive to the inhibition of L-NAME. Dihydroethidium staining revealed an increased intravascular superoxide production in db/db, attenuated by L-NAME and Saxa, and abrogated by apocynin. The dimer/monomer ratio of endothelial NOS was decreased in db/db mice and restored by Saxa. Cyclooxygenase-1 and thromboxane-A2 receptor expression, higher in db/db, was down-regulated by Saxa. Met treatment did not modify any of the abnormal vascular responses. Saxa reverses vascular hypertrophic remodeling and ameliorates NO availability in small arteries from db/db mice through the abrogation of NAD(P)H oxidase-driven eNOS uncoupling and by reducing the action of cyclooxygenase-1-derived vasoconstrictors downregulating the expression of thromboxane-prostanoid receptors.