4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Activation of Transient Receptor Potential Channel Vanilloid 4 by DPP-4 (Dipeptidyl Peptidase-4) Inhibitor Vildagliptin Protects Against Diabetic Endothelial Dysfunction.

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Endothelial dysfunction is an early step to the progression of cardiovascular diseases in diabetes. Apart from their anti-diabetic action, DPP-4 (dipeptidyl peptidase-4) inhibitors also reduce cardiovascular events in diabetic patients. However, the underlying mechanism of the beneficial effect of DPP-4 inhibitor on endothelial function is still obscure. In this study, we intervened type 1 or 2 diabetic model mice with vildagliptin for 4 weeks and measured the vascular reactivity. We found that vildagliptin improved endothelium-dependent vasodilation in diabetic mice independent of GLP-1 (glucagonlike peptide-1), but this effect was blocked by a SIRT1 (Sirtuin 1) inhibitor, Ex527. Mechanistically, vildagliptin-activated Transient Receptor Potential Channel Vanilloid 4 (TRPV4) to promote extracellular calcium uptake in endothelial cells, which activated AMPK (AMP-activated protein kinase)/SIRT1 pathway to counteract hyperglycemia-induced endothelial reactive oxygen species generation and senescence. Vildagliptin directly binds to TRPV4 by forming a hydrogen bond, which is critical to vildagliptin-evoked endothelial calcium intake. Knockout or inhibition of TRPV4 erased the beneficial role of vildagliptin. In addition, activation of SIRT1 by SRT1720 improved endothelial function independent of TRPV4 and reduced TRPV4 transcription to maintain an appropriate calcium level. In summary, our findings prove that vildagliptin protects against hyperglycemia-induced endothelial dysfunction by activating TRPV4-meditaed Ca2+ uptake, which helps to re-understand the mechanism of DPP-4 inhibitors and expand the therapeutic scope.

          Related collections

          Author and article information

          Journal
          Hypertension
          Hypertension (Dallas, Tex. : 1979)
          Ovid Technologies (Wolters Kluwer Health)
          1524-4563
          0194-911X
          January 2020
          : 75
          : 1
          Affiliations
          [1 ] From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., Xiao Wei, Y.H., H.W., T.M., Xing Wei, L.W., Z.Y., D.L., Z.Z.).
          [2 ] Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China (L.L., Y.S., G.-H.D.).
          [3 ] Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, China (M.W., Q.Z., X.F., G.Y.).
          [4 ] Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing, China (H.Z.).
          Article
          10.1161/HYPERTENSIONAHA.119.13778
          31735085
          a3c27614-1c73-4ba0-b0c8-b5128901ecdc
          History

          diabetes complications,sirtuin 1,transient receptor potential channels,vascular endothelial cells,vildagliptin

          Comments

          Comment on this article