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Cardiomyocyte-speci...
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Laudette, MarionGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
(author)
Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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2023-03-06
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Oxford University Press (OUP),2023
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:kth-335367
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-335367URI
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https://doi.org/10.1093/cvr/cvad041DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-104809URI
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https://gup.ub.gu.se/publication/325060URI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20230907
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Aims Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CMPcsk9−/− mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Methods and results Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9−/− mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9−/− hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9−/− mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9−/− mice. Circulating lipid levels were unchanged in CM-Pcsk9−/− mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9−/− mice had an increased number of mitochondria–endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. Conclusion PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Lindbom, Malin,1976Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xlorem
(author)
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Arif, MuhammadKTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden(Swepub:kth)u1vvaean
(author)
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Cinato, MathieuGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xcinma
(author)
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Ruiz, Mario,1984Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xruima
(author)
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Doran, StephenFaculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome Interactions, King’s College London, London WC2R 2L2, UK,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom
(author)
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Miljanovic, Azra,1979Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xisiaz
(author)
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Rutberg, Mikael,1959Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xrutmi
(author)
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Andersson, Linda,1973Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xanlin
(author)
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Klevstig, MartinaGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xklevs
(author)
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Henricsson, Marcus,1975Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xstahm
(author)
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Bergh, Per-OlofGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xbpero
(author)
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Bollano, EntelaDepartment of Cardiology, Sahlgrenska University Hospital, Gothenburg 41345, Sweden,Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden, Sahlgrenska University Hospital, Gothenburg, Sweden
(author)
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Aung, NayWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London SW15 5PN, UK; Barts Heart Centre, St Bartholomew’s Hospital, Barts Health National Health Service Trust, West Smithfield EC1A 7BE, UK,William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, United Kingdom; Barts Heart Centre, St Bartholomew's Hospital, Barts Health National Health Service Trust, West Smithfield, London, United Kingdom
(author)
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Smith, J. Gustav,1982Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsmigu
(author)
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Pilon, Marc,1966Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xpilom
(author)
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Hyötyläinen, Tuulia,1971-Örebro universitet,Institutionen för naturvetenskap och teknik,School of Natural Sciences and Technology, Örebro University, Örebro 70182, Sweden(Swepub:oru)tihn
(author)
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Oresic, Matej,1967-Örebro universitet,Institutionen för medicinska vetenskaper,School of Medical Sciences, Örebro University, Örebro 70182, Sweden; Turku Bioscience Centre, University of Turku, Turku 20520, Finland(Swepub:oru)moc
(author)
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Perkins, Rosie,1965Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xperro
(author)
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Mardinoglu, AdilKTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome Interactions, King’s College London, London WC2R 2L2, UK,Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom(Swepub:kth)u1t8kmr6
(author)
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Levin, Malin,1973Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xlevim
(author)
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Borén, Jan,1963Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xborej
(author)
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Göteborgs universitetInstitutionen för medicin, avdelningen för molekylär och klinisk medicin
(creator_code:org_t)
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In:Cardiovascular Research: Oxford University Press (OUP)119:7, s. 1537-15520008-63631755-3245
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Laudette, Marion
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Lindbom, Malin, ...
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Arif, Muhammad
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Cinato, Mathieu
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Ruiz, Mario, 198 ...
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Doran, Stephen
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Miljanovic, Azra ...
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Rutberg, Mikael, ...
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Andersson, Linda ...
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Klevstig, Martin ...
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Henricsson, Marc ...
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Bergh, Per-Olof
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Bollano, Entela
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Aung, Nay
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Smith, J. Gustav ...
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Pilon, Marc, 196 ...
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Hyötyläinen, Tuu ...
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Oresic, Matej, 1 ...
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Perkins, Rosie, ...
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Mardinoglu, Adil
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Levin, Malin, 19 ...
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Borén, Jan, 1963
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Cardiovascular R ...
- By the university
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Royal Institute of Technology
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Örebro University
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University of Gothenburg