Dataset Information

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

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.

SUBMITTER: Andersson L

PROVIDER: S-EPMC8599074 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Andersson Linda L Cinato Mathieu M Mardani Ismena I Miljanovic Azra A Arif Muhammad M Koh Ara A Lindbom Malin M Laudette Marion M Bollano Entela E Omerovic Elmir E Klevstig Martina M Henricsson Marcus M Fogelstrand Per P Swärd Karl K Ekstrand Matias M Levin Max M Wikström Johannes J Doran Stephen S Hyötyläinen Tuulia T Sinisalu Lisanna L Orešič Matej M Tivesten Åsa Å Adiels Martin M Bergo Martin O MO Proia Richard R Mardinoglu Adil A Jeppsson Anders A Borén Jan J Levin Malin C MC

European heart journal 20211101 43

<h4>Aims</h4>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 ...[more]

PMID: 34297830

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Dataset Information

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

Aims

Methods and results

Conclusions

Publications

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

Similar Datasets

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