Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse caveolin-3 knockout hearts

ABSTRACT: Energy Substrate Uptake and Metabolism are Preserved in Hypertrophic Caveolin-3 Knockout Hearts Experiment Overall Design: 3 wild types, 3 knockouts

ORGANISM(S): Mus musculus

SUBMITTER: Michael Lisanti

PROVIDER: E-GEOD-10848 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts.

Augustus Ayanna S AS Buchanan Jonathan J Addya Sankar S Rengo Giuseppe G Pestell Richard G RG Fortina Paolo P Koch Walter J WJ Bensadoun Andre A Abel E Dale ED Lisanti Michael P MP

American journal of physiology. Heart and circulatory physiology 20080613 2

Caveolin-3 (Cav3), the primary protein component of caveolae in muscle cells, regulates numerous signaling pathways including insulin receptor signaling and facilitates free fatty acid (FA) uptake by interacting with several FA transport proteins. We previously reported that Cav3 knockout mice (Cav3KO) develop cardiac hypertrophy with diminished contractile function; however, the effects of Cav3 gene ablation on cardiac substrate utilization are unknown. The present study revealed that the uptak ...[more]

PMID: 18552160

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Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome.

Dataset Information

Transcription profiling of mouse caveolin-3 knockout hearts

Publications

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts.

Similar Datasets

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