title: Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism.
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.
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. liu_limei@126.com
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.forename: Yi-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Pu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Zhen Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Chi Fai
authors.initials: CF
authors.lastname: Ng
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018027:Receptors, Glucagon / Q000819:agonists; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D014688:Venoms; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D000068900:Sitagliptin Phosphate