Abstract 065: Soluble Dipeptidyl Peptidase-4 Induces Endothelial Dysfunction by the Release of Vasoconstrictor Prostanoids: Protective Effect of Dipeptidyl Peptidase Inhibitors

Abstract

Soluble dipeptidyl peptidase (sDPP)-4 is a novel adipokine whose release is increased in patients with the metabolic syndrome. This study aimed to explore the capacity of sDPP-4 to directly impair vascular reactivity, which is considered as an early hallmark of endothelial dysfunction. As determined using a small vessel myograph, sDPP-4 (20-500 ng/mL) did not affect the contractility to noradrenaline (3 nmol/L to 30 μmol/L) in isolated murine mesenteric microvessels. sDPP-4 did not modify either the endothelium-independent relaxations induced by sodium nitroprusside (1 nmol/L to 100 μmol/L) in microvessels precontracted with 3 μmol/L noradrenaline. However, sDPP-4 impaired in a concentration-dependent manner the endothelium-dependent relaxation elicited by acetylcholine (ACh; 1 nmol/L to 10 μmol/L) with pD2 values of 6.88±0.17, 6.86±0.25, 6.24±0.18, 5.54±0.31 for 0, 20, 100 and 200 ng/mL sDPP-4, respectively. At 500 ng/mL sDPP-4, the maximal relaxation induced by ACh was reduced from 78.20±8.83% to 20.29±3.94%. The inhibition of cyclooxygenase or the blockade of thromboxane TP receptors with indomethacin (10 μmol/L) and SQ29548 (100 nmol/L), respectively, prevented the impaired relaxation to ACh evoked by a submaximal concentration of sDPP-4 (200 ng/mL). In line with these results, sDPP-4 (500 ng/mL) stimulated the release of thromboxane A2 (TXA2) by cultured human coronary artery endothelial cells (HCAEC) from 1.64±0.21 to 3.60±0.70 pg/mL. The DPP-4 inhibitors K579 (100 nmol/L) and linagliptin (10 nmol/L) prevented both TXA2 release and the impaired relaxation caused by sDPP-4. In conclusion, sDPP-4 arises as a causative agent of endothelial dysfunction through the release of COX-derived vasoconstrictor prostanoids. By interfering with such deleterious action of sDPP-4, pharmacological DPP-4 inhibitors might help preventing impaired endothelial function in type 2 diabetes mellitus or the metabolic syndrome.