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

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

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

Adiels Martin
Andersson Linda
Arif Muhammad
Bergo Martin O
Bollano Entela
Borén Jan
Cinato Mathieu
Doran Stephen
Ekstrand Matias
Fogelstrand Per
Henricsson Marcus
Hyötyläinen Tuulia
Jeppsson Anders
Klevstig Martina
Koh Ara
Laudette Marion
Levin Malin C
Levin Max
Lindbom Malin
Mardani Ismena
Mardinoglu Adil
Miljanovic Azra
Omerovic Elmir
Orešič Matej
Proia Richard
Sinisalu Lisanna
Swärd Karl
Tivesten Åsa
Wikström Johannes
Katso/Avaa
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OXFORD UNIV PRESS
doi:10.1093/eurheartj/ehab412
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022012710651
Tiivistelmä

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.

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