King's College London

Research portal

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Research output: Contribution to journalArticlepeer-review

Linda Andersson, Mathieu Cinato, Ismena Mardani, Azra Miljanovic, Muhammad Arif, Ara Koh, Malin Lindbom, Marion Laudette, Entela Bollano, Elmir Omerovic, Martina Klevstig, Marcus Henricsson, Per Fogelstrand, Karl Swärd, Matias Ekstrand, Max Levin, Johannes Wikström, Stephen Doran, Tuulia Hyötyläinen, Lisanna Sinisalu & 9 more Matej Orešič, Åsa Tivesten, Martin Adiels, Martin O. Bergo, Richard Proia, Adil Mardinoglu, Anders Jeppsson, Jan Borén, Malin C. Levin

Original languageEnglish
Pages (from-to)4481-4492
Number of pages12
JournalEuropean Heart Journal
Volume42
Issue number43
DOIs
Published14 Nov 2021

Bibliographical note

Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

King's Authors

Abstract

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454