Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-α in Pacing-Induced Heart Failure

Osorio, Juan C.; Stanley, William C.; Linke, Axel; Castellari, M; Diep, Quy N.; Panchal, Ashish R.; Hintze, Thomas H.; Lopaschuk, Gary D.; Recchia, Fabio A.

doi:10.1161/01.cir.0000023531.22727.c1

Cited by 305 publications

(280 citation statements)

References 37 publications

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“…We chronically instrumented 16 male mongrel dogs (25-28 kg, 1-2 yr of age) to measure left ventricular and aortic pressure and coronary flow and to place epicardial pacing leads on the left ventricular free wall as previously described (16,23,25). The dogs were divided in three groups: six were subjected to left ventricular pacing at 210 beats/min for 3 wk; six were paced for 210 beats/min for 3 wk and at 240 beats/min thereafter; four were not paced and used as normal controls.…”

Section: Methodsmentioning

confidence: 99%

Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

Ojaimi

Qanud

Hintze

et al. 2007

Physiological Genomics

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Ojaimi C, Qanud K, Hintze TH, Recchia FA. Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs. Physiol Genomics 29: 76 -83, 2007. First published December 12, 2006; doi:10.1152/physiolgenomics.00159.2006.-Our aim was to determine the changes in the gene expression profile occurring during the transition from compensated dysfunction (CD) to decompensated heart failure (HF) in pacing-induced dilated cardiomyopathy. Twelve chronically instrumented dogs underwent left ventricular pacing at 210 beats/min for 3 wk and at 240 beats thereafter, and four normal dogs were used as control. The transition from CD to HF occurred between the 3rd and 4th wk of pacing, with end-stage HF at 28 Ϯ 1 days. RNA was extracted from left ventricular tissue at control and 3 and 4 wk of pacing (n ϭ 4) and tested with the Affymetrix Canine Array. We found 509 genes differentially expressed in CD vs. control (P Յ 0.05, fold change ՆϮ2), with 362 increasing and 147 decreasing; 526 genes were differentially expressed in HF vs. control (P Յ 0.05; fold change ՆϮ2), with 439 increasing and 87 decreasing. To better understand the transition, we compared gene alterations at 3 vs. 4 wk pacing and found that only 30 genes differed (P Յ 0.05; fold change of Ϯ2). We conclude that a number of processes including normalization of gene regulation during decompensation, appearance of new upregulated genes and maintenance of gene expression all contribute to the transition to overt heart failure with an unexpectedly small number of genes differentially regulated. heart failure; pacing dog; microarray OVER THE PAST YEARS OTHER authors and we have used chronically instrumented dogs with high-frequency cardiac pacing to study pathophysiological and molecular mechanisms related to the development of dilated cardiomyopathy. This model of congestive heart failure is characterized by a very predictable evolution and reproduces many key features of the human disease, including progressive ventricular chambers dilation and wall thinning, decreased contractility, neurohormonal activation, beta adrenergic desensitization, and altered metabolism (19). In particular, we could determine functional and metabolic changes occurring only between the 3rd and 4th wk of pacing, i.e., during the transition from compensated to decompensated failure (25). The marked cardiac functional impairment and systemic deterioration observed during this relatively short phase of transition suggests the occurrence of profound molecular alterations. Their identification would provide notable insights in the pathophysiology and clinical management of heart failure. Unfortunately, given the complexity of the heart failure syndrome, such molecular changes are likely very numerous and interrelated, while most studies have been focused on single or selected groups of molecules, due to the limitations of the classical methods of analysis.More recently, global gene transcript profiling has emerged as a powerful tool f...

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Section: Methodsmentioning

confidence: 99%

Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

Ojaimi

Qanud

Hintze

et al. 2007

Physiological Genomics

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“…In rodent models of pressure overload hypertrophy, expression of PPARα and PGC-1α is reduced in the hypertrophied and failing heart and in hypertrophied cardiac myocytes in culture (82)(83)(84)(85)(86)(87). Levels of the PPAR partner, RXRα, are also reduced in a canine pacing-induced model of heart failure and by hypoxia in cardiac myocytes (88,89). Interestingly, a reciprocal induction of transcription factors, including chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and Sp1 and Sp3, which repress promoter activity of key FAO enzyme genes, is observed in hypertrophy and heart failure models and is thought to contribute to the reduction in myocardial FAO (82,90).…”

Section: Perturbations In Pgc-1/ppar Signaling In the Hypertrophied Amentioning

confidence: 99%

Mitochondrial energy metabolism in heart failure: a question of balance

Huss¹,

Kelly²

2005

J. Clin. Invest.

185

208

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"Mitochondrial energy metabolism in heart failure: A question of balance." The Journal of Clinical Investigation. 115,3. 547-555. (2005 The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure. IntroductionAll cellular processes are driven by ATP-dependent pathways. The heart has perpetually high energy demands related to the maintenance of specialized cellular processes, including ion transport, sarcomeric function, and intracellular Ca 2+ homeostasis. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux, yet the heart has a limited capacity for substrate storage. Thus, ATP-generating pathways must respond proportionately to dynamic fluctuations in physiological demands and fuel delivery. The time frame of such metabolic regulatory responses ranges from seconds to minutes (acute) or hours to days (chronic) and involves regulation at multiple levels, including allosteric control of enzyme activity via metabolic intermediates, signal transduction events, and the regulation of genes encoding rate-limiting enzymes and proteins. Metabolic regulation is inextricably linked with cardiac function. This metabolism-function relationship is relevant to diseases that lead to cardiac hypertrophy and heart failure. The progression to heart failure of any cause is associated with a gradual but progressive decline in the activity of mitochondrial respiratory pathways leading to diminished capacity for ATP production. Reduced capacity for energy transduction leads to secondary dysregulation of cellular processes critical for cardiac pump function, including Ca 2+ handling and contractile function, which results in a downward spiral of increased energy demand and diminished function. Evidence has emerged that energy deficiency can be a cause and an effect of heart failure. Cardiac metabolic regulatory events may also be adaptive in certain disease states. For example, in the ischemic heart, a reduction in mitochondrial oxidative capacity serves to reduce oxygen consumption in the context of limited O 2 availability. Many of the metabolic regulatory events that dictate fuel selection and capacity for ATP production in the normal and failing heart occur at the level of gene expression. The consequence of specific metabolic gene regulatory events as adaptive versus

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“…115 While the levels of PPARa in the failing heart are not different from those in normal myocardium, the expression of RXRa has been shown to be suppressed in the failing state. 116 Acute phase response (APR) is also characterized by reduced uptake and oxidation of fatty acids in the liver and the heart. A potent inducer of APR and sepsis, the endotoxin LPS has been shown to markedly downregulate all three RXR isoforms and a number of nuclear hormone receptors and coactivators, including PPARa, TR and PGC-1.…”

Section: Role Of Rxrs In Cardiac Musclementioning

confidence: 99%

Retinoid X receptors: X-ploring their (patho)physiological functions

Szántó

Narkar²,

Shen³

et al. 2004

Cell Death Differ

256

242

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Retinoid X receptor (RXR) belongs to a family of ligandactivated transcription factors that regulate many aspects of metazoan life. A class of nuclear receptors requires RXR as heterodimerization partner for their function. This places RXR in the crossroad of multiple distinct biological pathways. This and the fact that the debate on the endogenous ligand requirement for RXR is not yet settled make RXR still an enigmatic transcription factor. Here, we review some of the biology of RXR. We place RXR into the evolution of nuclear receptors, review structural details and ligands of the receptor. Then processes regulated by RXR are discussed focusing on the developmental roles deduced from studies on knockout animals and metabolic roles in diseases such as diabetes and atherosclerosis deduced from pharmacological studies. Finally, aspects of RXR's involvement in myeloid differentiation and apoptosis are summarized along with issues on RXR's suitability as a therapeutic target.

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Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-α in Pacing-Induced Heart Failure

Cited by 305 publications

References 37 publications

Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

Mitochondrial energy metabolism in heart failure: a question of balance

Retinoid X receptors: X-ploring their (patho)physiological functions

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