The Role of DPP4 Activity in Cardiovascular Districts: In Vivo and In Vitro Evidence

Abstract

The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus.

DPP4 in Cardiometabolic Disease

“…DPP4 is expressed on endothelial cells and seems to play a physiological role in the regulation of vascular tone and angiogenesis. 54 Studies have suggested that DPP4/incretin axis has substantial implication in cardiovascular system ( Figure 3).…”

Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of subclinical atherosclerosis in Chinese patients with newly diagnosed type 2 diabetes: A cross-sectional study

“…Thus, increased DPP4 activities in the individuals with high subclinical atherosclerosis risk may not be merely a consequence of enhanced inflammation and oxidative stress. Considering the multiple pleiotropic effects of DPP4 activity and its high expression in circulation and endothelial cells [3,46], the mutual effects between DPP4 activities and other unknown factors might also exert some influence on the development of subclinical atherosclerosis in type 2 diabetes.…”

Vascular effects of linagliptin in non‐obese diabetic mice are glucose‐independent and involve positive modulation of the endothelial nitric oxide synthase (eNOS)/caveolin‐1 (CAV‐1) pathway

“…The GLP‐1R‐dependent hypothesis is based on the finding that DPP‐4 inhibition, by inducing an increase in GLP‐1, promotes its interaction with GLP‐1R expressed in the endothelium . This event activates a downstream signal transduction that includes cAMP production and K ATP channel activation . The receptor‐independent hypothesis postulates a direct involvement of DPP‐4 in vascular reactivity.…”

“…22,23 This event activates a downstream signal transduction that includes cAMP production and K ATP channel activation. 24,25 The receptor-independent hypothesis postulates a direct involvement of DPP-4 in vascular reactivity. In line with this latter hypothesis, it has been shown that DPP-4 is expressed in the vascular endothelium 25 and its inhibition induces a direct vasorelaxant effect on isolated vessels in vitro in the presence of GLP-1R antagonist.…”