Control by Circulating Factors of Mitochondrial Function and Transcription Cascade in Heart Failure

Garnier, Anne; Zoll, Joffrey; Fortin, D.; N’guessan, Benoit Banga; Lefebvre, Florence; Gény, Bernard; Mettauer, Bertrand; Veksler, Vladimir; Ventura‐Clapier, Renée

doi:10.1161/circheartfailure.108.812099

Cited by 70 publications

(56 citation statements)

References 52 publications

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“…Indeed, doxorubicin treatment also altered mitochondria more severely in males, as evidenced by the downregulation of gene expression of mitochondrial 39 PGC-1α and its targets are downregulated in different experimental models of heart failure and in patients. 40,41 The same was found in daunorubicin-treated male rabbits. 14 In the present study, PGC-1β seemed a relevant target of doxorubicin in males because its downregulation is also observed at the onset of cardiac toxicity.…”

Section: Discussionsupporting

confidence: 62%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

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114

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Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

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Section: Discussionsupporting

confidence: 62%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

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114

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“…Importantly, PGC-1␣ is lower in the failing heart. The report by Garnier et al, 4 in this issue shows that ET-1 and angiotensin II downregulate whereas aldosterone and isoprenaline upregulate PGC-1␣ expression in ventricular myocytes. NRF indicates nuclear respiratory factors; ERR, estrogen receptors; PPAR, peroxisome proliferator-activated receptors; RXR, retinoid receptors.…”

Section: Rat Ventricular Myocytesmentioning

confidence: 80%

“…A study by Scheubel et al, 12 in which mitochondrial enzyme activities were found to be unchanged in human failing hearts, normalized activities to CS activity. Importantly, the data presented by Garnier et al 4 show that CS, a good marker of mitochondrial mass, also decreased. Normalizing cyclooxygenase and CK activities to CS activity in the Garnier et al 4 study would show the same apparently misleading result.…”

Section: Human Myocardiummentioning

confidence: 86%

On the Control of Metabolic Remodeling in Mitochondria of the Failing Heart

Ingwall

2009

Circ: Heart Failure

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T he metabolic phenotype of the failing heart may be defined as follows. 1 Metabolism remodels in the failing heart, leading to a loss in energy reserve and the inability to increase ATP supply. Ultimately, this metabolic rigidity leads to a fall in ATP. The likely time line is decreased energy reserve via the phosphotransferase reactions (creatine kinase [CK] and adenylate kinase) leading to increases in ADP and AMP, triggering an increase in glycolysis. Although the contribution of glycolysis to overall ATP synthesis increases at least in the hypertrophied heart, glycolytic reserve is limited. Importantly, as heart failure evolves, ATP synthesis from oxidation of both endogenous and exogenous fatty acids by mitochondria, the major source of ATP in the heart, falls. 2 Article see p 342Remodeling of the failing myocardium is controlled by energy sensors such as AMP that lead to changes in phosphorylation state (as well as other chemical modifications) of many proteins for short-term preservation of ATP and by activation of transcription factors that coordinately control long-term remodeling of entire ATP synthesis and utilizing pathways.Given that the requirement for ATP for all metabolic processes and for cell viability is absolute, a renewed interest in metabolism has led to identification of the molecular links between physiological and metabolic stimuli and the regulation of gene expression in the heart. We not only have identified the metabolic targets of specific nuclear receptors and DNA-binding transcriptional activators but also are beginning to learn how their signals are amplified and sustained to remodel metabolism.Transcription is activated when transcriptional activators, including peroxisome proliferator-activated receptors, estrogen receptors, retinoid receptors, nuclear respiratory factors, and myocyte-enhancing factor-2 (MEF-2) form proteinprotein complexes with the peroxisome proliferator-activated receptor-␥ coactivators, namely PGC-1␣ and ␤, tethering PGC-1s to DNA (Figure). When complexed with the transcription activators, PGC-1s activate genes encoding proteins comprising entire metabolic pathways that control ATP synthesis in mitochondria (fatty acid uptake, ␤-oxidation, oxidative phosphorylation, the Krebs cycle, and electron transport chain), phosphoryl transfer (sarcomeric mitochondrial CK and adenine nucleotide transporter), glucose uptake and utilization, and ATP-utilizing proteins (Figure). The different transcription factors confer specificity of PGC-1s for its genomic targets. Substantial overlap exists, and there is much to learn about the full range of targets. Because of its central role in transcriptional control of metabolism, PGC-1␣ is referred to as a master regulator.PGC-1␣ is itself regulated. For example, the cyclindependent kinases Cdk9 and Cdk7 target PGC-1␣, thereby conferring additional specificity for the transcriptional control of ATP synthesizing and utilizing reactions. Other known regulators of PGC-1␣ in striated muscle include p38 mitogenactivated protein kina...

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“…Among several targets for redox-dependent Ang-II actions in skeletal muscle, modulation of insulin/insulin-like growth factor (IGF) pathway (Brink et al, 2001) and mitochondrial biogenesis (Garnier et al, 2009;Mitsuishi et al, 2009) seem to play an important role. For example Ang-II infusion into mice resulted in a down-regulation of circulating IGF-1, and the local over expression of IGF-1 prevented Ang-II mediated proteolysis and skeletal muscle apoptosis (Song et al, 2005).…”

Section: Introductionmentioning

confidence: 99%