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Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats
with streptozotocin-induced diabetes by suppressing the nuclear factor-?B/I?B?
system through the activation of AMP-activated protein kinase
#MMPMID27122056
Tang ST
; Su H
; Zhang Q
; Tang HQ
; Wang CJ
; Zhou Q
; Wei W
; Zhu HQ
; Wang Y
Int J Mol Med
2016[Jun]; 37
(6
): 1558-66
PMID27122056
show ga
Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors,
including sitagliptin, exert favourable effects on the vascular endothelium.
DPP-4 inhibitors suppress the degradation of glucagon-like peptide-1 (GLP?1),
which has been reported to enhance nitric oxide (NO) production. However, the
effects of DPP-4 inhibitors on endothelin-1 (ET-1) expression in the aorta, as
well as the underlying mechanisms responsible for these effects, have yet to be
investigated in animal models of diabetes mellitus (DM). In the present study,
the rats were randomly divided into the following four groups: i) control;
ii) DM; iii) DM + low?dose sitagliptin (10 mg/kg); and iv) DM + high?dose
sitagliptin (30 mg/kg). Apart from the control group, all the rats received a
high-fat diet for 8 weeks prior to the induction of diabetes with an
intraperitoneal injection of streptozotocin. The treatments were then
administered for 12 weeks. The serum levels of ET-1, NO, GLP-1 and insulin were
measured as well as endothelial function. The expression of ET-1, AMP-activated
protein kinase (AMPK) and nuclear factor (NF)-?B/I?B? were determined. After
12 weeks of treatment, the diabetic rats receiving sitagliptin showed
significantly elevated serum levels of GLP-1 and NO, and reduced levels of ET-1.
Moreover, sitagliptin significantly attenuated endothelial dysfunction as well as
the remodeling of the aortic wall. Notably, sitagliptin inhibited ET-1 expression
at the transcriptional and translational level in the aorta, which may have been
mediated by the suppression of the NF-?B/I?B? system induced by AMPK activation.
The majority of the above-mentioned effects were dose dependent. Taken together,
the findings of the present study indicate that sitagliptin inhibits ET-1
expression in the aortic endothelium by suppressing the NF-?B/I?B? system through
the activation of the AMPK pathway in diabetic rats. These findings further
demonstrate some of the vasoprotective properties of DPP-4 inhibitors in vivo.
|AMP-Activated Protein Kinases/genetics/metabolism
[MESH]
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