Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism

Limei Liu, Jian Liu, Wing Tak Wong, Xiao Yu Tian, Chi Wai Lau, Yi Xiang Wang, Gang Xu, Yunfei Pu, Zhiming Zhu, Aimin Xu, Karen S.L. Lam, Zhen Yu Chen, Chi Fai Ng, Xiaoqiang Yao, Yu Huang

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

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 endothelium-dependent 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-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, 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. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

Original languageEnglish (US)
Pages (from-to)833-841
Number of pages9
JournalHypertension
Volume60
Issue number3
DOIs
StatePublished - Sep 2012

Keywords

  • NO
  • dipeptidyl peptidase 4
  • endothelium-dependent relaxation
  • glucagon-like peptide 1
  • protein kinases
  • spontaneously hypertensive rats

ASJC Scopus subject areas

  • Internal Medicine

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