Di-peptidyl peptidase-4 inhibitor sitagliptin protects vascular function in metabolic syndrome: possible role of epigenetic regulation.
Metabolic syndrome (MetS) is a complex medical disorder characterized by insulin resistance, hypertension, and high risk of coronary disease and stroke. Microvascular rarefaction and endothelial dysfunction have also been linked with MetS, and recent evidence from clinical studies supports the efficacy of incretin-based antidiabetic therapies for vascular protection in diabetes. Previous studies pointed out the importance of dipeptidyl peptidase-4 (DPP-4) inhibition in endothelial cells due to getting protection against metabolic pathologies. We therefore aimed to investigate the acute effects of a DPP-4 inhibitor, sitagliptin, on vascular function in rats with high-sucrose diet-induced MetS. In order to elucidate the mechanisms implicated in the effects of DPP-4 inhibition, we tested the involvement of NO pathway and epigenetic regulation in the MetS. Acute use of sitagliptin protects the vascular function in the rats with MetS in part due to NO pathway via restoring the depressed aortic relaxation responses mediated by receptors. Application of sitagliptin enhanced the depressed phosphorylation levels of both the endothelial NO synthase and the apoptotic status of protein kinase B, known as Akt, in endothelium-intact thoracic aorta from rats with MetS. One-hour application of sitagliptin on aortic rings from rats with MetS also induced remarkable histon posttranslational modifications such as increased expression of H3K27Me3, but not of H3K27Me2, resulting in an accumulation of the H3K27Me3. Our findings suggest that, in addition to its well-known hypoglycemic action, sitagliptin may also have beneficial effects on hyperglycemia-induced vascular changes in an endotheium-dependent manner. These present results with sitagliptin aside from the glycaemic control, may demonstrate its important role in the treatment of patients with MetS.
Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
Figen Amber
FA
Cicek
Cicek Figen
CF
Amber
Zeynep
Z
Tokcaer-Keskin
Tokcaer-Keskin
TK
Zeynep
Evren
E
Ozcinar
Ozcinar
O
Evren
Yosuf
Y
Bozkus
Bozkus
B
Yusuf
Kamil Can
KC
Akcali
Akcali Kamil
AK
Can
Belma
B
Turan
Turan
T
Belma
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000187:drug effects; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D000068900:Sitagliptin Phosphate; D013395:Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D014230:Triazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D054873:Dipeptidyl-Peptidase IV Inhibitors; D006657:Histones; D011719:Pyrazines; D014230:Triazoles; D013395:Sucrose; D000068900:Sitagliptin Phosphate