Effects of dipeptidyl peptidase 4 inhibition on the endothelial control of the vascular tone

Abstract

Dipeptidyl peptidase 4 (DPP4) is a serine protease known to cleave incretin hormones, which stimulate insulin secretion after food intake, a fact that supported the development of its inhibitors (DPP4i or gliptins) for the treatment of type 2 diabetes mellitus. In addition to their glucose-lowering effects, DPP4i show benefits for the cardiovascular system that could be related, at least in part, to their protective action on vascular endothelium. DPP4i have been associated with the reversal of endothelial dysfunction, an important predictor of cardiovascular events and a hallmark of diseases such as atherosclerosis, diabetes mellitus, hypertension, and heart failure. In animal models of these diseases, DPP4i increase nitric oxide bioavailability and limits oxidative stress, thereby improving the endothelium-dependent relaxation. Similar effects on flow-mediated dilation and attenuation of endothelial dysfunction have also been noted in human studies, suggesting a value for gliptins in the clinical scenario, despite the variability of the results regarding the DPP4i used, treatment duration, and presence of comorbidities. In this mini-review, we discuss the advances in our comprehension of the DPP4i effects on endothelial regulation of vascular tone. Understanding the role of DPP4 and its involvement in the signaling mechanisms leading to endothelial dysfunction will pave the way for a broader use of DPP4i in conditions that endothelial dysfunction is a pivotal pathophysiological player.

Keywords: DPP-IV; cardiovascular diseases; eNOS; gliptins; reactive oxygen species.

Graphical abstract

Figure 1.

Signaling mechanisms impacted by DPP4 inhibition in ECs. A: a macroscopic scheme demonstrating that under healthy conditions, vascular tone is achieved by a balance between vasoconstrictors [such as angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [nitric oxide (NO) and prostacyclin (PGI2)], with a strong contribution of ECs. Disease states impair this balance by a direct effect on NO synthesis and secretion by ECs, leading to EC dysfunction (blue cells), reduced NO bioavailability, ROS generation, and inflammatory cell infiltration, ultimately impairing endothelium-dependent relaxation (EDR) and increasing smooth muscle cell contraction. These effects are reversed upon treatment with DPP4 inhibitors (DPP4i), mainly by restoring NO bioavailability and mitigating the signaling mechanisms underlying ROS formation. B: signaling mechanisms impacted by DPP4 inhibition in ECs. DPP4 cleaves GLP-1, limiting the activation of the GLP-1 receptor (GLP-1R). This inhibition is relieved by DPP4i, allowing GLP-1-GLP-1R binding and the downstream activation of adenylyl cyclase (AC), increasing cAMP and activating the protein kinase A (PKA). Active PKA can phosphorylate eNOS, increasing NO generation. A PKA binding motif is also found in the eNOS gene (NOS3), which may contribute to the restoration of eNOS levels in dysfunctional ECs exposed to DPP4i. GLP-1R also activates the cAMP-liver kinase B (LKB)-AMPK and the phosphoinositide 3-kinase (PI3K)-pyruvate dehydrogenase kinase (PDK1)-Akt signaling pathways, both of which positively regulate eNOS by phosphorylation, leading to NO synthesis. Reduced eNOS expression, PI3K-PDK1-Akt signaling, and lncRNA ENSMUST00000155383 expression (with whom Cacna1C, Itgav, Itga8, and Npnt are coexpressed) are observed in dysfunctional ECs and restored upon DPP4 inhibition. In addition, the DPP4i vildagliptin (dark green) has been demonstrated to activate the transient receptor potential cation channel subfamily V member 4 (TRPV4), restoring calcium influx and calmodulin (CaM)-calcium/calmodulin-dependent protein kinase (CaMKKβ)-AMPK-SIRT1 signaling. Calcium influx and CaM are required to sustained eNOS activity. SIRT1 is thought to mediate the antagonizing effects of DPP4i in ROS signaling and in the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent inflammatory genes in dysfunctional ECs. In addition to transmembrane DPP4, a soluble DPP4 (sDPP4) can be generated by matrix metalloproteinases. sDPP4 carries a SLIG amino acid motif, capable of binding and activating the protease-activator receptor 2 (PAR2), involved in the positive regulation of cyclooxygenase 2 (COX2), which generates thromboxane A2, a vasoconstrictor. This signaling, like the signaling mechanisms elicited by membrane DPP4, can be inhibited by DPP4i. DPP4, dipeptidyl peptidase 4; EC, endothelial cell; eNOS endothelial nitric oxide synthase; GLP-1, glucagon-like peptide-1; ROS, reactive oxygen species.