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Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia
Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Level 4, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Madrid, Spain.
Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom.
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2011 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 92, no 1, p. 29-38Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2011. Vol. 92, no 1, p. 29-38
Keywords [en]
Mitochondria; Cardiac arrhythmia; Peroxisome proliferator-activated receptor-gamma coactivator 1 beta; Metabolic disease; Lysophosphatidylcholine
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:oru:diva-63650DOI: 10.1093/cvr/cvr155ISI: 000294969000007PubMedID: 21632884Scopus ID: 2-s2.0-80052902603OAI: oai:DiVA.org:oru-63650DiVA, id: diva2:1169214
Funder
Wellcome trust
Note

Funding agencies:

British Heart Foundation

Medical Research Council

European Commission (MITIN) HEALTH-F4-2008-223450

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-02-20Bibliographically approved

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Oresic, Matej

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