Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon–Like Peptide 1–Dependent Mechanism

Abstract

Abstract-Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endotheliumdependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-␣ and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-␣, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. 1 Hypertension can cause renal damage if it is not properly controlled.2 The impaired vasodilator response is a risk factor for renal function loss in patients with essential hypertension.3 Persistent hypertension alters functional characteristics of vascular endothelial cells and is associated with impaired vasodilatory function.4 Diminished production and function of endothelium-derived NO leads to endothelial dysfunction, 5 a crucial initial step culminating in vascular events in hypertension.Dipeptidyl peptidase 4 (DPP-4), also known as CD26, is a ubiquitous enzyme detectable in the endothelium.6 Glucagonlike peptide 1 (GLP-1) produced by L-type cells in the intestine, is a substrate for DPP-4. 7 GLP-1 improves glucose use in patients with type 2 diabetes mellitus by increasing insulin secretion and inhibiting glucagon secretion. 8,9 Sitagliptin, a highly selective DPP-4 inhibitor, 10 inhibits the inactivation and degradation of GLP-1, 11 which is used for the treatment of type 2 diabetes mellitus as monotherapy or in combination with other antiglycemic agents, such as metformin. 12The effect of GLP-1 on blood pressure has been reported in both animal and human hypertension.

Protection of Glucagon-Like Peptide-1 in Cisplatin-Induced Renal Injury Elucidates Gut-Kidney Connection

“…46 Limei et al reported that DPP-4 inhibitor sitagliptin administered to hypertensive rats spontaneously improved endothelial function by restoring nitric oxide bioavailability. 47 Glorie et al reported that DPP-4 inhibitor vildagliptin attenuated AKI in a rat ischemia-reperfusion model. 20 Although the mechanisms of action of DPP-4 inhibition on ischemic AKI were not clarified in the above-mentioned reports, we clarified for the first time that a GLP-1-mediated antiapoptotic effect contributed to renal protection in a mouse CP-AKI model.…”

Sitagliptin attenuates inflammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

“…DPP-4 inhibitors may improve cardiac outcomes following myocardial infarction via cytoprotective pathways (15). Notably, DPP-4 inhibitors have been demonstrated to exert antiatherogenic effects on improving endothelial function through augmenting GLP-1 activity, and the anti-inflammatory effect of DPP-4 inhibitors has been suggested in preclinical and clinical studies of type 2 diabetes and coronary artery disease (16,17). However, the role of DPP-4 inhibitors in septic inflammation, which may lead to cardiovascular complications, remains unclear.…”

Circulating dipeptidyl peptidase-4 activity is associated with insulin resistance in type 1 diabetic patients

“…In support to our study results, Yang et al (2014) [28] have recently demonstrated that DPP4 activity is significantly higher in healthy subjects with higher blood pressure and insulin resistance determinated by HOMA-IR index in apparently healthy Chinese man and woman. Recent experimental and clinical studies suggest that DPP4 inhibition reduces blood pressure [29] although the underlying mechanism remains poorly understood. Currently, there are evidence that DPP4 inhibition leads to increased nitric-oxide (NO) bioavailability but the question whether the it occurs in a direct or indirect pathway indicating the potential role of DPP4 substrates, especially via glucagon-like peptide-1 (GLP-1) receptor [30,31].…”