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

19 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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Lysophospholipids
Cardiac Arrhythmias
Metabolic Diseases
Ventricular Tachycardia
Isoproterenol
Action Potentials
Homeostasis
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Lysophosphatidylcholines
Oxidative Phosphorylation
Organelle Biogenesis
Electron Transport
Ion Channels
Adrenergic Agents
Membrane Potentials
Muscle Cells
Type 2 Diabetes Mellitus
Hypertrophy
Energy Metabolism
Genes

Cite this

Gurung, I. S., Medina-Gomez, G., Kis, A., Baker, M., Velagapudi, V., Guha Neogi, S., ... 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
Gurung, Iman S. ; Medina-Gomez, Gema ; Kis, Adrienn ; Baker, Michael ; Velagapudi, Vidya ; Guha Neogi, Sudeshna ; Campbell, Mark ; Rodriguez-Cuenca, Sergio ; Lelliott, Christopher ; McFarlane, Ian ; Orešič, Matej ; Grace, Andrew A. ; Vidal-Puig, Antonio ; Huang, Christohper L.-H. / Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia. In: Cardiovascular Research. 2011 ; Vol. 92, No. 1. pp. 29-38.
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title = "Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia",
abstract = "AimsPeroxisome 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 resultsMicroarray 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.ConclusionPGC1β−/− 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.",
author = "Gurung, {Iman S.} and Gema Medina-Gomez and Adrienn Kis and Michael Baker and Vidya Velagapudi and {Guha Neogi}, Sudeshna and Mark Campbell and Sergio Rodriguez-Cuenca and Christopher Lelliott and Ian McFarlane and Matej Orešič and Grace, {Andrew A.} and Antonio Vidal-Puig and Huang, {Christohper L.-H.}",
year = "2011",
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language = "English",
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Gurung, IS, Medina-Gomez, G, Kis, A, Baker, M, Velagapudi, V, Guha Neogi, S, Campbell, M, Rodriguez-Cuenca, S, Lelliott, C, McFarlane, I, Orešič, M, Grace, AA, Vidal-Puig, A & Huang, CL-H 2011, 'Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia', Cardiovascular Research, vol. 92, no. 1, pp. 29-38. https://doi.org/10.1093/cvr/cvr155

Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia. / Gurung, Iman S. (Corresponding Author); Medina-Gomez, Gema; Kis, Adrienn; Baker, Michael; Velagapudi, Vidya; Guha Neogi, Sudeshna; Campbell, Mark; Rodriguez-Cuenca, Sergio; Lelliott, Christopher; McFarlane, Ian; Orešič, Matej; Grace, Andrew A.; Vidal-Puig, Antonio (Corresponding Author); Huang, Christohper L.-H.

In: Cardiovascular Research, Vol. 92, No. 1, 2011, p. 29-38.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia

AU - Gurung, Iman S.

AU - Medina-Gomez, Gema

AU - Kis, Adrienn

AU - Baker, Michael

AU - Velagapudi, Vidya

AU - Guha Neogi, Sudeshna

AU - Campbell, Mark

AU - Rodriguez-Cuenca, Sergio

AU - Lelliott, Christopher

AU - McFarlane, Ian

AU - Orešič, Matej

AU - Grace, Andrew A.

AU - Vidal-Puig, Antonio

AU - Huang, Christohper L.-H.

PY - 2011

Y1 - 2011

N2 - AimsPeroxisome 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 resultsMicroarray 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.ConclusionPGC1β−/− 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.

AB - AimsPeroxisome 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 resultsMicroarray 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.ConclusionPGC1β−/− 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.

U2 - 10.1093/cvr/cvr155

DO - 10.1093/cvr/cvr155

M3 - Article

VL - 92

SP - 29

EP - 38

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -

Gurung IS, Medina-Gomez G, Kis A, Baker M, Velagapudi V, Guha Neogi S et al. Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia. Cardiovascular Research. 2011;92(1):29-38. https://doi.org/10.1093/cvr/cvr155