Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart

Sack, Michael N.; Rader, Toni A.; Park, Sonhee; Bastin, Jean; McCune, Sylvia A.; Kelly, Daniel P.

doi:10.1161/01.cir.94.11.2837

Cited by 617 publications

(470 citation statements)

References 34 publications

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“…Reports of patients and animal models with heart failure have consistently shown that the myocardium switches to increased dependency on glucose as the substrate during cardiac hypertrophy and failure (29). This metabolic shift coincides with a down-regulation of expression of fatty acid oxidation enzymes and has been interpreted as a reactivation of the fetal gene expression program (31). The knockout mice of this study display an early onset of reduced expression of PPAR␣ transcripts, encoding the major regulator of the fatty acid oxidation pathway.…”

Section: Discussionmentioning

confidence: 99%

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

Hansson

Hance

Dufour

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

204

148

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We performed global gene expression analyses in mouse hearts with progressive respiratory chain deficiency and found a metabolic switch at an early disease stage. The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate. These characteristics were observed after 2 weeks of age and became gradually more severe until the terminal stage occurred at 10 -12 weeks of age. Global gene expression analyses with microarrays showed that a metabolic switch occurred early in the progression of cardiac mitochondrial dysfunction. A large number of genes encoding critical enzymes in fatty acid oxidation showed decreased expression whereas several genes encoding glycolytic enzymes showed increased expression. These alterations are consistent with activation of a fetal gene expression program, a well-documented phenomenon in cardiac disease. An increase in mitochondrial mass was not observed until the disease had reached an advanced stage. In contrast to what we have earlier observed in respiratory chain-deficient skeletal muscle, the increased mitochondrial biogenesis in respiratory chain-deficient heart muscle did not increase the overall mitochondrial ATP production rate. The observed switch in metabolism is unlikely to benefit energy homeostasis in the respiratory chain-deficient hearts and therefore likely aggravates the disease. It can thus be concluded that at least some of the secondary gene expression alterations in mitochondrial cardiomyopathy do not compensate but rather directly contribute to heart failure progression.

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Section: Discussionmentioning

confidence: 99%

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

Hansson

Hance

Dufour

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

204

148

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“…After birth, the capacity for PPAR-␣-dependent FAO increases markedly. This results in the heart using FAO as the preferred substrate for ATP production while retaining the ability to switch to glucose and lactate utilization to meet its energy demands with varying dietary and physiological conditions (74,94). Studies using cultured neonatal cardiomyocytes have demonstrated the direct effects of fatty acids and PPAR-␣ agonists in activating PPAR-␣-dependent enzymes of fatty acid uptake and FAO in the heart (10,91,92).…”

Section: Ppar-␣ and The Heartmentioning

confidence: 99%

“…In conditions of pressure-induced cardiac hypertrophy, PPAR-␣ is downregulated, resulting in reversion of the heart to the fetal pattern of glucose and lactate substrate utilization (4,74). Diminished cardiac FAO and increased utilization of glucose has been found in studies of both murine (73) and human (19) cardiac hypertrophy.…”

Section: Ppar-␣ and The Heartmentioning

confidence: 99%

PPAR-α effects on the heart and other vascular tissues

Francis

Annicotte²,

Auwerx³

2003

American Journal of Physiology-Heart and Circulatory Physiology

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Peroxisome proliferator-activated receptor (PPAR)-α is a member of a large nuclear receptor superfamily whose main role is to activate genes involved in fatty acid oxidation in the liver, heart, kidney, and skeletal muscle. While currently used mainly as hypolipidemic agents, the cardiac effects and anti-inflammatory actions of PPAR-α agonists in arterial wall cells suggest other potential cardioprotective and antiatherosclerotic effects of these agents. This review summarizes current knowledge regarding the effects of PPAR-α agonists on lipid and lipoprotein metabolism, the heart, and the vessel wall and introduces some of the insights gained in these areas from studying PPAR-α-deficient mice. The introduction of new and more potent PPAR-α agonists will provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and prevention of vascular disease.

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“…Isolated mitochondria from Cn*-expressing hearts demonstrated impaired oxidative function (16). These latter observations are inconsistent with the known metabolic responses in skeletal muscle given that, during pathological hypertrophic growth, the heart undergoes a reversion to a fetal energy metabolic program characterized by reduction of mitochondrial oxidative capacity and fatty acid utilization (17)(18)(19). In contrast, with physiological forms of hypertrophy such as following exercise training, Cn and CaMK are activated yet both contractile and metabolic function is preserved (20).…”

mentioning

confidence: 96%

Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle

Schaeffer¹,

Wende²,

Magee³

et al. 2004

Journal of Biological Chemistry

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To learn more about the targets of Cn (Cn) and calcium/calmodulin-dependent protein kinase in cardiac muscle, we investigated their actions in cultured cardiac myocytes and the hearts of mice in vivo. Adenoviral-mediated expression of constitutively active forms of either pathway induced expression of peroxisome proliferator-activated receptor ␥ coactivator 1␣, a transcriptional coactivator involved in the control of multiple cellular energy metabolic pathways in cardiac myocytes. Transcriptional profiling studies demonstrated that Cn and calcium/calmodulin-dependent protein kinase activate distinct but overlapping metabolic gene regulatory programs. Expression of the nuclear receptor, peroxisome proliferator-activated receptor ␣, was markedly increased by Cn, but not calcium/calmodulin-dependent protein kinase, providing one mechanism whereby cellular fatty acid utilization genes are selectively activated by Cn. Transfection experiments demonstrated that Cn directly activates the mouse peroxisome proliferator-activated receptor ␣ gene promoter. Co-transfection "add-back" experiments demonstrated that the transcription factors, myocyte enhancer factors 2C or 2D, were sufficient to confer Cn-mediated activation of the peroxisome proliferatoractivated receptor ␣ gene. Cn was also shown to directly activate a known peroxisome proliferator-activated receptor ␣ target, muscle-type carnitine palmitoyltransferase I, providing a second mechanism by which Cn activates genes of cellular fatty acid utilization. Lastly, the gene expression of peroxisome proliferator-activated receptor ␥ coactivator 1␣ and peroxisome proliferator-activated receptor ␣ was reduced in the hearts of mice with cardiac-specific ablation of the Cn regulatory subunit. These data support a role for calcium-triggered signaling pathways in the regulation of cardiac energetics and identify pathway-specific control of metabolic targets.Skeletal muscle fiber types are defined by contractile protein isoform composition and energy metabolic properties. Slowtwitch muscle fibers possess greater mitochondrial volume supporting higher oxidative metabolic capacity compared with fast-twitch fibers. Muscle metabolic phenotype is plastic, responding to numerous external stimuli. Calcium signaling serves an important role in the adaptive response of skeletal muscle to external stimuli, including fiber type determination. Evidence has emerged that calcium-triggered regulatory pathways acting through Cn (Cn), 1 a serine/threonine protein phosphatase, and calcium/calmodulin-dependent protein kinases (CaMK), serve a major role in determining the functional and metabolic phenotype of skeletal muscle by transducing alterations in cytosolic calcium concentration. In support of this, Chin et al. (1) demonstrated that a constitutively active form of Cn (Cn*) is capable of activating transcription of slow fiberspecific gene promoters. Similarly, overexpression of Cn* in skeletal muscle results in an increase in slow muscle fiber types (2), and in CnA␣ and A␤ null mice there ...

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Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart

Abstract: These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.

Cited by 617 publications

References 34 publications

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

PPAR-α effects on the heart and other vascular tissues

Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle

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