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

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; Matej Orešič; Åsa Tivesten; Martin Adiels; Martin O. Bergo; Richard Proia; Adil Mardinoglu; Anders Jeppsson; Jan Borén; Malin C. Levin

doi:10.1093/eurheartj/ehab412

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

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 SinisaluMatej Orešič, Åsa Tivesten, Martin Adiels, Martin O. Bergo, Richard Proia, Adil Mardinoglu, Anders Jeppsson, Jan Borén, Malin C. Levin^*

^*Corresponding author for this work

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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.

Original language	English
Pages (from-to)	4481-4492
Number of pages	12
Journal	European Heart Journal
Volume	42
Issue number	43
DOIs	https://doi.org/10.1093/eurheartj/ehab412
Publication status	Published - 14 Nov 2021

Keywords

Adrenergic
Autophagy
Beta
Cardiac dysfunction
Endolysosomal trafficking
Glycosphingolipids
Lipids
Receptors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/eurheartj/ehab412

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Andersson, L., Cinato, M., Mardani, I., Miljanovic, A., Arif, M., Koh, A., Lindbom, M., Laudette, M., Bollano, E., Omerovic, E., Klevstig, M., Henricsson, M., Fogelstrand, P., Swärd, K., Ekstrand, M., Levin, M., Wikström, J., Doran, S., Hyötyläinen, T., ... Levin, M. C. (2021). Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking. European Heart Journal, 42(43), 4481-4492. https://doi.org/10.1093/eurheartj/ehab412

@article{4625b0e5e1a2409bb57919c4bee9332b,

title = "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.",

keywords = "Adrenergic, Autophagy, Beta, Cardiac dysfunction, Endolysosomal trafficking, Glycosphingolipids, Lipids, Receptors",

author = "Linda Andersson and Mathieu Cinato and Ismena Mardani and Azra Miljanovic and Muhammad Arif and Ara Koh and Malin Lindbom and Marion Laudette and Entela Bollano and Elmir Omerovic and Martina Klevstig and Marcus Henricsson and Per Fogelstrand and Karl Sw{\"a}rd and Matias Ekstrand and Max Levin and Johannes Wikstr{\"o}m and Stephen Doran and Tuulia Hy{\"o}tyl{\"a}inen and Lisanna Sinisalu and Matej Ore{\v s}i{\v c} and {\AA}sa Tivesten and Martin Adiels and Bergo, {Martin O.} and Richard Proia and Adil Mardinoglu and Anders Jeppsson and Jan Bor{\'e}n and Levin, {Malin C.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2021",

month = nov,

day = "14",

doi = "10.1093/eurheartj/ehab412",

language = "English",

volume = "42",

pages = "4481--4492",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "43",

}

Andersson, L, Cinato, M, Mardani, I, Miljanovic, A, Arif, M, Koh, A, Lindbom, M, Laudette, M, Bollano, E, Omerovic, E, Klevstig, M, Henricsson, M, Fogelstrand, P, Swärd, K, Ekstrand, M, Levin, M, Wikström, J, Doran, S, Hyötyläinen, T, Sinisalu, L, Orešič, M, Tivesten, Å, Adiels, M, Bergo, MO, Proia, R, Mardinoglu, A, Jeppsson, A, Borén, J & Levin, MC 2021, 'Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking', European Heart Journal, vol. 42, no. 43, pp. 4481-4492. https://doi.org/10.1093/eurheartj/ehab412

TY - JOUR

T1 - Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

AU - Andersson, Linda

AU - Cinato, Mathieu

AU - Mardani, Ismena

AU - Miljanovic, Azra

AU - Arif, Muhammad

AU - Koh, Ara

AU - Lindbom, Malin

AU - Laudette, Marion

AU - Bollano, Entela

AU - Omerovic, Elmir

AU - Klevstig, Martina

AU - Henricsson, Marcus

AU - Fogelstrand, Per

AU - Swärd, Karl

AU - Ekstrand, Matias

AU - Levin, Max

AU - Wikström, Johannes

AU - Doran, Stephen

AU - Hyötyläinen, Tuulia

AU - Sinisalu, Lisanna

AU - Orešič, Matej

AU - Tivesten, Åsa

AU - Adiels, Martin

AU - Bergo, Martin O.

AU - Proia, Richard

AU - Mardinoglu, Adil

AU - Jeppsson, Anders

AU - Borén, Jan

AU - Levin, Malin C.

PY - 2021/11/14

Y1 - 2021/11/14

N2 - 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.

AB - 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.

KW - Adrenergic

KW - Autophagy

KW - Beta

KW - Cardiac dysfunction

KW - Endolysosomal trafficking

KW - Glycosphingolipids

KW - Lipids

KW - Receptors

UR - http://www.scopus.com/inward/record.url?scp=85113835337&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehab412

DO - 10.1093/eurheartj/ehab412

M3 - Article

C2 - 34297830

AN - SCOPUS:85113835337

SN - 0195-668X

VL - 42

SP - 4481

EP - 4492

JO - European Heart Journal

JF - European Heart Journal

IS - 43

ER -

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

Abstract

Keywords

UN SDGs

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