Cardiac accumulation of citrate during brief myocardial ischaemia and reperfusion in the pig <i>in vivo</i>

Hassel,; Ilebekk,; Tønnessen,

doi:10.1046/j.1365-201x.1998.0400e.x

Cited by 22 publications

(16 citation statements)

References 33 publications

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“…Increased iron-dependent toxicity due to citrate may explain the observation that biochemical parameters of damage in mouse cardiomyocytes occur before histochemically measurable iron accumulation (2). Much of the tissue damage in ischemia-reperfusion injury also is due to increased cytosolic iron, because iron chelation reduces tissue pathology (39)(40)(41), but during ischemia reperfusion there is also a 4-to 6-fold increase in citrate (42). Our results suggest that the combination of iron and citrate promotes tissue injury.…”

Section: Discussionmentioning

confidence: 64%

Genetic analysis of iron citrate toxicity in yeast: Implications for mammalian iron homeostasis

Chen

Hemenway

Kaplan

2002

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

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Deletion of the yeast homologue of frataxin, YFH1, results in mitochondrial iron accumulation and respiratory deficiency (petite formation). We used a genetic screen to identify mutants that modify iron-associated defects in respiratory activity in ⌬yfh1 cells. A deletion in the peroxisomal citrate synthase CIT2 in ⌬yfh1 cells decreased the rate of petite formation. Conversely, overexpression of CIT2 in ⌬yfh1 cells increased the rate of respiratory loss. Citrate toxicity in ⌬yfh1 cells was dependent on iron but was independent of mitochondrial respiration. Citrate toxicity was not restricted to iron-laden mitochondria but also occurred when iron accumulated in cytosol because of impaired vacuolar iron storage. These results suggest that high levels of citrate may promote iron-mediated tissue damage.T he yeast YFH1 gene and its mammalian orthologue, frataxin, are nuclear genes that encode mitochondrial proteins (1). In humans, mutations in frataxin are responsible for the neurologic and cardiac disease Friedreich's ataxia (2). The most common mutation of frataxin is an expansion of a GAA triplet within the first intron of the frataxin gene (3). The effect of the triplet expansion is to reduce frataxin transcription and protein concentration. Although the frataxin protein is highly conserved in eukaryotes, there is no consensus regarding the function of Yfh1p͞frataxin. Suggested roles for the protein include mitochondrial iron storage (4, 5), iron-sulfur biosynthesis (2, 6), regulation of respiration (7), and control of antioxidant defenses (8). Although the function of Yfh1p͞frataxin is unknown, it is thought that the pathophysiology of the human disorder results from a mitochondrial defect (9). In yeast, a deficit of Yfh1p leads to accumulation of mitochondrial iron, which reacts with oxygen metabolites to generate oxygen radicals, resulting in a respiratory deficit (1, 10). We used a genetic screen to identify genes that would preserve the respiratory activity of ⌬yfh1 cells. We report that deletion of CIT2, a gene that encodes an extramitochondrial citrate synthase, can markedly attenuate the iron toxicity in ⌬yfh1 cells and preserve respiratory activity. Alternatively, overexpression of CIT2 can induce toxicity when iron accumulates in either the mitochondria or in the cytosol, the latter as a result of impaired iron storage. Although extracellular citrate is an iron chelator, these results suggest that intracellular citrate iron complexes are toxic. Materials and MethodsStrains, Growth Media, and Plasmids. DY150 [MATa,112,] and DY1457 [MAT␣,112, ade6,] were derived from the W303 strain of Saccharomyces cerevisiae. The METYFH1 strain [⌬yfh1, pMET3YFH1[URA3] (a yfh1 strain that has a plasmid containing the YFH1 gene controlled by the MET3 promoter in a vector that has a URA3 gene)] was generated by crossing the ⌬yfh1 [MATa,112,, yfh1::HIS3] strain with DY1457 as described (10). The expression of YFH1 was inhibited by growing cells in complete synthetic media (CM) supplemented with methionine (330 g͞ml).Gene de...

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Section: Discussionmentioning

confidence: 64%

Genetic analysis of iron citrate toxicity in yeast: Implications for mammalian iron homeostasis

Chen

Hemenway

Kaplan

2002

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

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“…Finally, metabolite changes observed in humans modulated the response to hypoxic injury in vitro, which suggests that these metabolites not only serve as markers, but may also modulate the evolving response to ischemia in vivo. The metabolic, structural, and functional consequences of ischemia and/or reperfusion have been examined in a wide variety of experimental animal models, including regional ischemia after coronary vessel occlusion in dogs (29)(30)(31) and swine (32)(33)(34)(35) as well as in humans with coronary disease (36)(37)(38)(39)(40) or undergoing heart surgery (41-43). However, prior studies have generally assayed relatively limited subsets of metabolites in focused approaches.…”

Section: Discussionmentioning

confidence: 99%

Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury

Lewis¹,

Wei²,

Liu³

et al. 2008

J. Clin. Invest.

256

197

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Emerging metabolomic tools have created the opportunity to establish metabolic signatures of myocardial injury. We applied a mass spectrometry-based metabolite profiling platform to 36 patients undergoing alcohol septal ablation treatment for hypertrophic obstructive cardiomyopathy, a human model of planned myocardial infarction (PMI). Serial blood samples were obtained before and at various intervals after PMI, with patients undergoing elective diagnostic coronary angiography and patients with spontaneous myocardial infarction (SMI) serving as negative and positive controls, respectively. We identified changes in circulating levels of metabolites participating in pyrimidine metabolism, the tricarboxylic acid cycle and its upstream contributors, and the pentose phosphate pathway. Alterations in levels of multiple metabolites were detected as early as 10 minutes after PMI in an initial derivation group and were validated in a second, independent group of PMI patients. A PMI-derived metabolic signature consisting of aconitic acid, hypoxanthine, trimethylamine N-oxide, and threonine differentiated patients with SMI from those undergoing diagnostic coronary angiography with high accuracy, and coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. Our results identify a role for metabolic profiling in the early detection of myocardial injury and suggest that similar approaches may be used for detection or prediction of other disease states.

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“…Coronary occlusion in an in vivo porcine model resulted in an abrupt 60% to 70% increase in myocardial citric acid content. 21 Furthermore, by cannulating the anterior interventricular vein in an in vivo porcine model, Panchal et al 22 demonstrated that an abrupt decrease in left anterior descending coronary artery flow resulted in an 80% decrease in citric acid efflux from the myocardium. These data support the notion that the metabolic changes that we observed are a direct consequence of myocardial ischemia and extend prior studies by their direct application to humans.…”

Section: Functional Pathway Analysismentioning

confidence: 99%

Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia

et al. 2005

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Background-Recognition of myocardial ischemia is critical both for the diagnosis of coronary artery disease and the selection and evaluation of therapy. Recent advances in proteomic and metabolic profiling technologies may offer the possibility of identifying novel biomarkers and pathways activated in myocardial ischemia. Methods and Results-Blood samples were obtained before and after exercise stress testing from 36 patients, 18 of whom demonstrated inducible ischemia (cases) and 18 of whom did not (controls). Plasma was fractionated by liquid chromatography, and profiling of analytes was performed with a high-sensitivity electrospray triple-quadrupole mass spectrometer under selected reaction monitoring conditions. Lactic acid and metabolites involved in skeletal muscle AMP catabolism increased after exercise in both cases and controls. In contrast, there was significant discordant regulation of multiple metabolites that either increased or decreased in cases but remained unchanged in controls.Functional pathway trend analysis with the use of novel software revealed that 6 members of the citric acid pathway were among the 23 most changed metabolites in cases (adjusted Pϭ0.04

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Cardiac accumulation of citrate during brief myocardial ischaemia and reperfusion in the pig in vivo

Cited by 22 publications

References 33 publications

Genetic analysis of iron citrate toxicity in yeast: Implications for mammalian iron homeostasis

Genetic analysis of iron citrate toxicity in yeast: Implications for mammalian iron homeostasis

Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury

Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia

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