Evidence map›Paper›PMID 36880401›Full record

ArticleCardiovascular research2023

Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.

Marion Laudette, Malin Lindbom, Muhammad Arif, Mathieu Cinato, Mario Ruiz, Stephen Doran, Azra Miljanovic, Mikael Rutberg, Linda Andersson, Martina Klevstig and 12 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cardiovascular research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
2.2field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 14 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 7 institutions in 3 countries.

Marion LaudetteDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Malin LindbomDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Muhammad ArifScience for Life Laboratory, Royal Institute of Technology, Stockholm 17165, Sweden.ORCID 0000-0003-2261-0881
Mathieu CinatoDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.ORCID 0000-0002-8490-4335
Mario RuizDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg 40530, Sweden.
Stephen DoranFaculty of Dentistry, Oral & Craniofacial Sciences, Centre for Host-Microbiome Interactions, King's College London, London WC2R 2L2, UK.ORCID 0000-0002-9236-5407
Azra MiljanovicDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Mikael RutbergDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Linda AnderssonDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Martina KlevstigDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Marcus HenricssonDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.ORCID 0000-0002-4202-0339
Per-Olof BerghDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Entela BollanoDepartment of Cardiology, Sahlgrenska University Hospital, Gothenburg 41345, Sweden.
Nay AungWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.ORCID 0000-0001-5095-1611
J Gustav SmithDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Marc PilonDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg 40530, Sweden.
Tuulia HyötyläinenSchool of Natural Sciences and Technology, Örebro University, Örebro 70182, Sweden.ORCID 0000-0002-1389-8302
Matej OrešičSchool of Medical Sciences, Örebro University, Örebro 70182, Sweden.
Rosie PerkinsDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Adil MardinogluScience for Life Laboratory, Royal Institute of Technology, Stockholm 17165, Sweden.
Malin C LevinDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Jan BorénDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.ORCID 0000-0003-0786-8091
University of Gothenburg · SESahlgrenska University Hospital · SEKing's College London · GBNational Health Service · GBÖrebro University · SEScience for Life Laboratory · SEUniversity of Turku · FI

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

aimsPro-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 (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. METHODS AND

resultsMice 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.

conclusionPCSK9, 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.

Indexed as

Myocytes, CardiacProprotein Convertase 9AnimalsEnergy MetabolismLipidsMiceMitochondriaReceptors, LDLSubtilisinLipidsPCSK9 protein, humanPcsk9 protein, mouseProprotein Convertase 9Receptors, LDLSubtilisinCardiac dysfunctionCardiomyocyteMetabolic inflexibilityMitochondriaPro-protein convertase subtilisin-kexin type 9 (PCSK9)

Identifiers

PMID36880401
PMCPMC10318396
OpenAlexW4323348650

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.