Article

Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia.

Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Cardiovascular research (impact factor: 5.8). 06/2011; 92(1):29-38. DOI:10.1093/cvr/cvr155 pp.29-38
Source: PubMed

ABSTRACT 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.
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.
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.

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Keywords

abnormal diastolic Ca(2+)
 
cardiac disease attributable
 
current injection
 
electron transport chain
 
inactivation characteristics
 
increased incidence
 
insulin resistance
 
Langendorff-perfused PGC1β(-/-)
 
lipidomic
 
Lipidomic analysis
 
lysophospholipid accumulation
 
lysophospholipid-induced cardiac lipotoxicity
 
oscillatory resting potentials
 
PGC1β modulate mitochondrial biogenesis
 
polymorphic ventricular tachycardia
 
pro-inflammatory lipid
 
transcriptional coactivators
 
type 2 diabetes
 
ventricular arrhythmic phenotype
 
ventricular tachycardia
 

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