Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia

Iman S. Gurung (Corresponding Author), Gema Medina-Gomez, Adrienn Kis, Michael Baker, Vidya Velagapudi, Sudeshna Guha Neogi, Mark Campbell, Sergio Rodriguez-Cuenca, Christopher Lelliott, Ian McFarlane, Matej Orešič, Andrew A. Grace, Antonio Vidal-Puig (Corresponding Author), Christohper L.-H. Huang

Research output: Contribution to journalArticleScientificpeer-review

20 Citations (Scopus)

Abstract

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 Ca2+ transients, whose amplitude and frequency were increased by isoprenaline, and Ca2+ 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 Ca2+-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 Ca2+ 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.
Original languageEnglish
Pages (from-to)29-38
JournalCardiovascular Research
Volume92
Issue number1
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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    Gurung, I. S., Medina-Gomez, G., Kis, A., Baker, M., Velagapudi, V., Guha Neogi, S., Campbell, M., Rodriguez-Cuenca, S., Lelliott, C., McFarlane, I., Orešič, M., Grace, A. A., Vidal-Puig, A., & Huang, C. L-H. (2011). Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia. Cardiovascular Research, 92(1), 29-38. https://doi.org/10.1093/cvr/cvr155