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

DOI Web Site 2 Citations
  • Peng Gao
    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.)
  • Li Li
    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.)
  • Xiao Wei
    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.)
  • Miao Wang
    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.)
  • Yangning Hong
    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.)
  • Hao Wu
    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.)
  • Yanjia Shen
    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.)
  • Tianyi Ma
    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.)
  • Xing Wei
    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.)
  • Qin Zhang
    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.)
  • Xia Fang
    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.)
  • Lijuan Wang
    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.)
  • Zhencheng Yan
    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.)
  • Guan-Hua Du
    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.)
  • Hongting Zheng
    Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing, China (H.Z.).
  • Gangyi Yang
    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.)
  • Daoyan Liu
    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.)
  • Zhiming Zhu
    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.)

Description

<jats:p> 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 Ca <jats:sup>2+</jats:sup> uptake, which helps to re-understand the mechanism of DPP-4 inhibitors and expand the therapeutic scope. </jats:p>

Journal

  • Hypertension

    Hypertension 75 (1), 150-162, 2020-01

    Ovid Technologies (Wolters Kluwer Health)

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