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Deletion of the met...
Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia
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- Gurung, Iman S. (author)
- Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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- Medina-Gomez, Gema (author)
- Metabolic Research Laboratories, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Madrid, Spain
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- Kis, Adrienn (author)
- Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Baker, Michael (author)
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom
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- Velagapudi, Vidya (author)
- VTT Technical Research Centre of Finland, Espo, Finland
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- Neogi, Sudeshna Guha (author)
- Genomics CoreLab, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Campbell, Mark (author)
- Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Rodriguez-Cuenca, Sergio (author)
- Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Lelliott, Christopher (author)
- Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom; Department of Bioscience, CVGI IMED, AstraZeneca R and D, Mölndal, Sweden
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- McFarlane, Ian (author)
- Genomics CoreLab, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Oresic, Matej, 1967- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,VTT Technical Research Centre of Finland, Espo, Finland
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- Grace, Andrew A. (author)
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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- Vidal-Puig, Antonio (author)
- Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
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- Huang, Christopher L-H. (author)
- Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom
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(creator_code:org_t)
- 2011-06-01
- 2011
- English.
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 92:1, s. 29-38
- Related links:
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- AIMS: Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases.METHODS AND RESULTS: Microarray analysis in mouse PGC1β(-/-) hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β(-/-) ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca(2+) transients, whose amplitude and frequency were increased by isoprenaline, and Ca(2+) currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K(+) currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca(2+)-calmodulin dependent protein kinase II expression.CONCLUSION: PGC1β(-/-) hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca(2+) homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Mitochondria; Cardiac arrhythmia; Peroxisome proliferator-activated receptor-gamma coactivator 1 beta; Metabolic disease; Lysophosphatidylcholine
Publication and Content Type
- ref (subject category)
- art (subject category)
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Gurung, Iman S.
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Medina-Gomez, Ge ...
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Kis, Adrienn
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Baker, Michael
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Velagapudi, Vidy ...
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Neogi, Sudeshna ...
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show more...
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Campbell, Mark
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Rodriguez-Cuenca ...
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Lelliott, Christ ...
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McFarlane, Ian
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Oresic, Matej, 1 ...
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Grace, Andrew A.
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Vidal-Puig, Anto ...
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Huang, Christoph ...
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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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Cardiovascular R ...
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Örebro University