Reactivation of Peroxisome Proliferator-activated Receptor α Is Associated with Contractile Dysfunction in Hypertrophied Rat Heart

Young, Martin E.; Laws, Frank A.; Goodwin, Gary W.; Taegtmeyer, Heinrich

doi:10.1074/jbc.m103826200

Cited by 237 publications

(186 citation statements)

References 32 publications

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“…Finck et al (11) showed that selective overexpression of PPAR-␣ in heart caused ventricular hypertrophy and systolic dysfunction. Young et al (37) showed that PPAR-␣ mRNA levels decrease in the heart of mice subjected to pressure overload, suggesting that downregulation of PPAR-␣ is part of the adaptive response of the hypertrophic heart. Similar effects on PPAR-␣ expression were observed in the CnA transgenic mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Two recent studies showed that increased PPAR-␣ activity in heart can cause cardiomyopathy (11,37). Finck et al (11) showed that selective overexpression of PPAR-␣ in heart caused ventricular hypertrophy and systolic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…5). Importantly, Young et al (37) showed that ligand-mediated reactivation of PPAR-␣ caused contractile dysfunction and heart failure in the pressure overload model. Among the genes induced by PPAR-␣ reactivation was PDK4 (37).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, Young et al (37) showed that ligand-mediated reactivation of PPAR-␣ caused contractile dysfunction and heart failure in the pressure overload model. Among the genes induced by PPAR-␣ reactivation was PDK4 (37). While multiple PPAR-␣ target genes undoubtedly contribute to the cardiomyopathy observed in both the Finck et al (11) and Young et al (37) studies, our results demonstrate that overexpression of PDK4 alone is sufficient to cause metabolic inflexibility and to exacerbate preexisting cardiomyopathy caused by chronic activation of the calcineurin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Zhao¹,

Jeoung²,

Burgess³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

106

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Kliewer SA. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294: H936-H943, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00870.2007.-The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway. fatty acid; hypertrophy; transgenic mice THERE IS A GROWING AWARENESS that systemic perturbations in energy metabolism such as those that occur in diabetes mellitus and other forms of metabolic disease contribute to cardiovascular disease (9). The healthy heart is a metabolic omnivore capable of switching between fatty acids and carbohydrates to match energy demands with dietary and physiological conditions (30, 31). Under conditions of pressure overload and cardiac hypertrophy, increased carbohydrate oxidation is part of the adaptive response to increased workload (21). However, in diabetes the metabolic flexibility of the heart is diminished, and it becomes more reliant on fatty acids for energy (10,21,30,31). This may contribute to functional derangements by causing oxidative stress and the accumulation of harmful lipid intermediates (10,21,30,31).In heart and other tissues, competition between fatty acids and carbohydrates occurs at the level of pyruvate dehydrogenase (PDH), which catalyzes the conversion of pyruvate to acetyl-CoA, thereby linking glycolysis to the Krebs cycle and ATP production. PDH is active when glucose oxidation prevails for the generation of energy and repressed when glucose is in short supply, such as during fasting (14). Regulation of PDH is accomplished by its interconversion between an active, nonphosphorylated form and an inactive, phosphorylated form. Phosphorylation and inactivation of PDH is mediated by a family of four PDH kinases (PDK1-4) (14, 29). Expression of one of these isozymes, PDK4, is rapidly and markedly induced in heart and other tissues in response to various metabolic stimuli, including fasting and a high-fat diet (28,33,34,36). Transcription ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Zhao¹,

Jeoung²,

Burgess³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

106

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“…Even though studies show mixed results [5,6], it is generally felt that the heart switches to a reliance on glycolysis as the primary pathway for energy production during the development of heart failure [7]. In the case of pressure 20 overload there is an increase in cardiac mass, re-expression of fetal genes, a suppression of genes related to several rate-limiting enzymes in fatty acid oxidation, enhancement of genes related to rate-limiting enzyme for glucose oxidation, and increased reliance on carbohydrate oxidation to enable maintenance of contractile function [8,9]. Also, an increased adrenergic tone in the setting of heart failure not only exerts a direct toxic effect on the myocyte [10] but also causes unfavorable changes in myocardial 25 energy use [11].…”

Section: Introductionmentioning

confidence: 99%

A study of changes in deformation and metabolism in the left ventricle as a function of hypertrophy in spontaneous hypertensive rats using microPET technology

Gullberg

Huesman

Reutter

et al. 2005

Journal of Nuclear Cardiology

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Problem: In the case of hypertrophy caused by pressure overload (hypertension) there is an increase in cardiac mass and modification cardiac metabolism. Aim: This study was designed to study the changes in glucose metabolism, ejection fraction, and deformation in the left ventricle with the progression of hypertrophy in spontaneous hypertensive rats (SHR). Methods: Dynamic PET data were acquired using the microPET II at UC Davis. Two rats were imaged at 10-week intervals for 18 months. Each time a dose of approximately 1-1.5 mCi of F-18-FDG was injected into a normotensive Wistar Kyoto (WKY) rat and the same dose was injected into a SHR rat. Each rat was imaged using a gated dynamic acquisition for 80 minutes acquiring list mode data with cardiac gating of approximately 600-900 million total counts. For the analysis of glucose of metabolism, the list mode data were histogrammed into a dynamic sequence (42 frames over 80 mins). For each time frame, projection data of 1203 140×210 sinograms of 0.582 mm bins were formed by summing the last three gates before and one after the R-wave trigger to correspond to the diastolic phase of the cardiac cycle. Dynamic sequences of 128×128×83 matrices of 0.4×0.4×0.582 mm 3 voxels in x, y, and z were reconstructed using an iterative MAP reconstruction which used a prior that penalized the high frequency components of the reconstruction using appropriate weighting between 26 nearest neighboring voxels. Time activity curves were generated from the dynamic reconstructed sequence for the blood and left ventricular tissue regions of interest which were fit to a 2-compartment model to obtain a least squares fit for the kinetic parameters. For the analysis of deformation, the list mode data were histogrammed into 8 gates of the cardiac cycle, each gate was the total sum of the later 60 mins of the 80 min acquisition. Images of 128×128×83 matrices for each gate were reconstructed using the same iterative MAP reconstruction used to reconstruct the dynamic sequence. The in-plane image dimensions were doubled to 256×256×83 in order to increase the resolution for the Warping analyses. These image data sets were then cropped to 128×128×83. The end-systolic image data sets were designated as the template images and the end-diastole image data sets were designated as the target images, thus providing an analysis of the diastolic relaxation and filling phases of the cardiac cycle. The template images were manually segmented to create surface definitions representing the epi-and endocardial surfaces. Finite element models of the left ventricles were created using the segmented surfaces and defining a transversely isotropic material with fiber angles varying from the epicardial surface to the endocardial surface. A Warping analyses was performed to obtain the LV strain tensor and fiber stretch distributions. Results: In one study, the average first principal Green-Lagrange strain, fiber stretch, ejection fraction, and metabolic rate of F-18-FDG was 0.22, 1.08, 80%, 0.1 for the WKY rat and...

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Metabolic Shifts during Aging and Pathology

2015

Comprehensive Physiology

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The heart is a very special organ in the body and has a high requirement for metabolism due to its constant workload. As a consequence, to provide a consistent and sufficient energy a high steady-state demand of metabolism is required by the heart. When delicately balanced mechanisms are changed by physiological or pathophysiological conditions, the whole system’s homeostasis will be altered to a new balance, which contributes to the pathologic process. So it is no wonder that almost every heart disease is related to metabolic shift. Furthermore, aging is also found to be related to the reduction in mitochondrial function, insulin resistance, and dysregulated intracellular lipid metabolism. Adenosine monophosphate-activated protein kinase (AMPK) functions as an energy sensor to detect intracellular ATP/AMP ratio and plays a pivotal role in intracellular adaptation to energy stress. During different pathology (like myocardial ischemia and hypertension), the activation of cardiac AMPK appears to be essential for repairing cardiomyocyte’s function by accelerating ATP generation, attenuating ATP depletion, and protecting the myocardium against cardiac dysfunction and apoptosis. In this overview, we will talk about the normal heart’s metabolism, how metabolic shifts during aging and different pathologies, and how AMPK regulates metabolic changes during these conditions.

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Reactivation of Peroxisome Proliferator-activated Receptor α Is Associated with Contractile Dysfunction in Hypertrophied Rat Heart

Cited by 237 publications

References 32 publications

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

A study of changes in deformation and metabolism in the left ventricle as a function of hypertrophy in spontaneous hypertensive rats using microPET technology

Metabolic Shifts during Aging and Pathology

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