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Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism.
Hypertension. 2012 Sep; 60(3):833-41.H

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+Show Affiliations

Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. liu_limei@126.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22868389

Citation

Liu, Limei, et al. "Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon-like Peptide 1-dependent Mechanism." Hypertension (Dallas, Tex. : 1979), vol. 60, no. 3, 2012, pp. 833-41.
Liu L, Liu J, Wong WT, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension. 2012;60(3):833-41.
Liu, L., Liu, J., Wong, W. T., Tian, X. Y., Lau, C. W., Wang, Y. X., Xu, G., Pu, Y., Zhu, Z., Xu, A., Lam, K. S., Chen, Z. Y., Ng, C. F., Yao, X., & Huang, Y. (2012). Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension (Dallas, Tex. : 1979), 60(3), 833-41. https://doi.org/10.1161/HYPERTENSIONAHA.112.195115
Liu L, et al. Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon-like Peptide 1-dependent Mechanism. Hypertension. 2012;60(3):833-41. PubMed PMID: 22868389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. AU - Liu,Limei, AU - Liu,Jian, AU - Wong,Wing Tak, AU - Tian,Xiao Yu, AU - Lau,Chi Wai, AU - Wang,Yi-Xiang, AU - Xu,Gang, AU - Pu,Yunfei, AU - Zhu,Zhiming, AU - Xu,Aimin, AU - Lam,Karen S L, AU - Chen,Zhen Yu, AU - Ng,Chi Fai, AU - Yao,Xiaoqiang, AU - Huang,Yu, Y1 - 2012/08/06/ PY - 2012/8/8/entrez PY - 2012/8/8/pubmed PY - 2013/1/8/medline SP - 833 EP - 41 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 60 IS - 3 N2 - 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. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/22868389/Dipeptidyl_peptidase_4_inhibitor_sitagliptin_protects_endothelial_function_in_hypertension_through_a_glucagon_like_peptide_1_dependent_mechanism_ L2 - http://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.112.195115?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -