| First Author | Gurung IS | Year | 2011 |
| Journal | Cardiovasc Res | Volume | 92 |
| Issue | 1 | Pages | 29-38 |
| PubMed ID | 21632884 | Mgi Jnum | J:191709 |
| Mgi Id | MGI:5462336 | Doi | 10.1093/cvr/cvr155 |
| Citation | Gurung IS, et al. (2011) Deletion of the metabolic transcriptional coactivator PGC1beta induces cardiac arrhythmia. Cardiovasc Res 92(1):29-38 |
| abstractText | AIMS: Peroxisome proliferator-activated receptor-gamma coactivators PGC1alpha and PGC1beta 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 PGC1beta(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases. METHODS AND RESULTS: Microarray analysis in mouse PGC1beta(-/-) 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. PGC1beta(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1beta(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1beta(-/-) 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: PGC1beta(-/-) 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. |
