Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon–Like Peptide 1–Dependent Mechanism
Open accessAbstract
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.
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Preclinical studies have documented inhibitory effects of GLP-1RAs on the development of atherosclerosis in animal models.
“Preclinical studies have documented the inhibitory effects of GLP-1RAs on the development of AS in animal models.443”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [443]
The Discussion and Perspectives report that the GLP-1R agonist exendin 4 improved endothelial function in hypertensive rats. They do not address whether GLP-1R agonists inhibit the development of atherosclerosis; a search for atherosclerosis found no passage establishing that outcome. (LLM, conf=0.76)
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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
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“443 These agents exert their anti-atherosclerotic effects through various mechanisms, including by improving blood lipid pro fi les, 444 preserving endothelial integrity and regulating endothelial function, 445 as well as modulating in fl ammatory processes.”
BackgroundType 2 Diabetes Mellitus and Hypertension
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- Authors
- 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. L., Chen, Z. Y., Ng, C. F., Yao, X., & Huang, Y.
- Affiliations
- Army Medical University (CN)
- From the Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (L.L., J.L., W.T.W., X.Y.T., C.W.L., X.Y., Y.H.), Departments of Imaging and Interventional Radiology (Y.-X.W.), Medicine and Therapeutics (G.X.), and Surgery (C.F.N.), and School of Life Sciences (Z.Y.C.), Chinese University of Hong Kong, Hong Kong, China; Department of Physiology and Pathophysiology (L.L.), Peking University Health Science Center, Beijing, China; Department of Hypertension and Endocrinology (Y.P.,...
- ORCID
- Venue
- Hypertension
- Published
- 2012-09
- Volume
- 60
- Issue
- 3
- Pages
- 833-841
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2168397692
- Cited by
- 179
- References
- 52
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 15 · 2020: 6 · 2019: 18 · 2018: 17 · 2017: 21 · 2016: 18 · 2015: 18 · 2014: 24 · 2013: 18 · 2012: 1
- FWCI
- 15.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- sitagliptin, DPP-4 inhibitors, glucagon-like peptide-1, GLP-1 receptor, endothelial function, renal artery, exendin-4, AMPK, protein kinase A, LKB1, endothelial nitric oxide synthase, nitric oxide bioavailability, adenylate cyclase, spontaneously hypertensive rats, renal blood flow
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Sitagliptin Phosphate, Exenatide, Cyclic AMP, Aged, Aged, 80 and over, Animals, Blood Pressure, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Humans, Hypertension, Kidney, Magnetic Resonance Imaging, Male, Middle Aged, Nitric Oxide, Peptides, Pyrazines, Rats, Inbred SHR, Rats, Inbred WKY, Regional Blood Flow, Renal Artery, Triazoles, Venoms, Signal Transduction, Receptors, Glucagon, Rats, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors, In Vitro Techniques
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