Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor traffickingScience for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Precision Medicine, School of Medicine, Sungkyunkwan University (SKKU), Suwon, Republic of Korea.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
Örebro University, School of Science and Technology.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Show others and affiliations
2021 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 42, no 43, p. 4481-4492Article in journal (Refereed) Published
Abstract [en]
AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.
METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.
CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.
Place, publisher, year, edition, pages
Oxford University Press, 2021. Vol. 42, no 43, p. 4481-4492
Keywords [en]
Cardiac dysfunction, Endolysosomal trafficking, Adrenergic, Autophagy, Beta, Glycosphingolipids, Lipids, Receptors
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:oru:diva-93133DOI: 10.1093/eurheartj/ehab412ISI: 000728161800014PubMedID: 34297830Scopus ID: 2-s2.0-85113835337OAI: oai:DiVA.org:oru-93133DiVA, id: diva2:1581730
Funder
Swedish Research Council, 2017-01340Swedish Heart Lung Foundation, 20170492
Note
Funding agency:
Sahlgrenska University Hospital ALF grants ALFGBG-724901
2021-07-252021-07-252022-04-01Bibliographically approved