Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia

Iman S. Gurung; 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; Christohper L.-H. Huang

doi:10.1093/cvr/cvr155

Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia

Iman S. Gurung^*
, 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^*
, Christohper L.-H. Huang

^*Corresponding author for this work

VTT Technical Research Centre of Finland

University of Cambridge
University of Cambridge, Addenbrooke's Hospital
VTT (former employee or external)

Research output: Contribution to journal › Article › Scientific › peer-review

30 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 language	English
Pages (from-to)	29-38
Journal	Cardiovascular Research
Volume	92
Issue number	1
DOIs	https://doi.org/10.1093/cvr/cvr155
Publication status	Published - 2011
MoE publication type	A1 Journal article-refereed

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SDG 3 Good Health and Well-being

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10.1093/cvr/cvr155

Cite this

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

@article{2b7448d29a554170a9d559d429ae7810,

title = "Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia",

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.",

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 Ore{\v s}i{\v c} and Grace, \{Andrew A.\} and Antonio Vidal-Puig and Huang, \{Christohper L.-H.\}",

year = "2011",

doi = "10.1093/cvr/cvr155",

language = "English",

volume = "92",

pages = "29--38",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "1",

}

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

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 - 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.

AB - 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.

U2 - 10.1093/cvr/cvr155

DO - 10.1093/cvr/cvr155

M3 - Article

SN - 0008-6363

VL - 92

SP - 29

EP - 38

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -

Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia

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