Hypotaurine Reduces Glucose‐Mediated Vascular Calcification

Acta Physiologica, vol. 241, pp. e70075

Abstract

AIM: Vascular calcification (VC), a characteristic feature of peripheral artery disease in patients with diabetes and chronic kidney disease, has been associated with poor prognosis. We hypothesize that hyperglycemia drives VC through alterations in metabolomic and transcriptomic profiles. METHODS: Human coronary artery smooth muscle cells (SMCs) were cultured with 0, 5.5, and 25 mM glucose under calcifying conditions. Untargeted metabolomic and transcriptomic analyses were performed at different time points. Mitochondrial respiration was examined using Seahorse analysis. RESULTS: Glucose-treated SMCs promoted extracellular matrix (ECM) calcification in a concentration- and time-dependent manner. The absence of glucose entirely abolished SMC calcification but reduced SMC proliferation in control and calcifying conditions compared to 25 mM glucose. Multi-omics data integration revealed key players from the hypotaurine/taurine metabolic pathway as the center hub of the reconstructed network. Glucose promoted the hypotaurine secretion, while its intracellular abundance was not altered. Blocking hypotaurine production by propargylglycine increased ECM calcification, while hypotaurine treatment prevented it. Furthermore, omics data suggest energy remodeling in calcifying SMCs under hyperglycemia. Calcifying SMCs exhibited decreased oxygen consumption that was partially restored by hypotaurine. Validation of our in vitro models using the murine warfarin model demonstrated reduced hypotaurine/taurine transporter (TAUT) expression in SMCs. CONCLUSIONS: Our multi-omics analysis revealed a role of the hypotaurine/taurine metabolic pathway in glucose-induced SMC calcification. Moreover, our data suggest a glucose-dependent energy remodeling in calcifying SMCs and that increasing glucose concentrations fuel ECM calcification. Our work highlights potential novel therapeutic targets that warrant further investigation in hyperglycemia-dependent in vitro SMC calcification.

Authors 10

1. Marina Augusto Heuschkel Aachen Department of Internal Medicine I‐Cardiology Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Department of Internal Medicine I – Cardiology Medical Faculty, RWTH Aachen University Aachen Germany

2. Armand M. G. Jaminon

   Maastricht University

   Affiliation as printed

   Department of Biochemistry Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands

   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands

3. Steffen Gräber
   Affiliation as printed

   Helmholtz Institute for Biomedical Engineering, Biointerface Lab Aachen Germany

   Helmholtz Institute for Biomedical Engineering, Biointerface Lab, Aachen, Germany

4. Anna Artati

   Helmholtz Munich

   Affiliation as printed

   Metabolomics and Proteomics Core Helmholtz Center Munich, German Research Center for Environmental Health Neuherberg Germany

   Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

5. Jerzy Adamski

   University of Ljubljana · National University of Singapore · Helmholtz Munich

   Affiliation as printed

   Department of Biochemistry Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubjana Slovenia

   Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health Neuherberg Germany

   Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubjana, Slovenia

   Institute of Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

6. Joachim Jankowski Aachen Institute for Molecular Cardiovascular Research IMCAR

   RWTH Aachen University

   Affiliation as printed

   Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University Aachen Germany

   Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University, Aachen, Germany

7. Leon J. Schurgers

   Maastricht University

   Affiliation as printed

   Department of Biochemistry Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands

   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands

8. Nikolaus Marx Aachen Department of Internal Medicine I‐Cardiology Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Department of Internal Medicine I – Cardiology Medical Faculty, RWTH Aachen University Aachen Germany

9. Willi Jahnen‐Dechent
   Affiliation as printed

   Helmholtz Institute for Biomedical Engineering, Biointerface Lab Aachen Germany

   Helmholtz Institute for Biomedical Engineering, Biointerface Lab, Aachen, Germany

10. Claudia Goettsch corresponding Aachen Department of Internal Medicine I‐Cardiology Medical Faculty

    Technische Universität Dresden · RWTH Aachen University

    Affiliation as printed

    Department of Internal Medicine I – Cardiology Medical Faculty, RWTH Aachen University Aachen Germany

    Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden Dresden Germany