Progressive Loss of Myocardial ATP Due to a Loss of Total Purines During the Development of Heart Failure in Dogs

Shen, Wen; Asai, Kuniya; Uechi, Masami; Mathier, Michael A.; Shannon, Richard P.; Vatner, Stephen F.; Ingwall, Joanne S.

doi:10.1161/01.cir.100.20.2113

Cited by 166 publications

(163 citation statements)

References 19 publications

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“…When our 31 P MRS data (Table 1) are combined with recent 1 H MRS measures showing reduced total Cr in comparable patients with heart failure (16.1 mol͞g of wet weight in CHF vs. 27.6 mol͞g of wet weight in healthy subjects) (13), myocardial free-ADP concentration calculated from the CK equilibrium reaction is 50% lower in failing hearts (Ϸ45 mol͞ liter) than in normal hearts (Ϸ92 mol͞liter, see Appendix). These in vivo estimates of ADP concentration argue against an increased ADP concentration in human heart failure and are consistent with the reduced ADP concentration observed in several animal studies noted above (41)(42)(43) as well as with in vitro data from end-stage human heart failure (36).…”

Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hesupporting

confidence: 87%

“…Because Cr is not synthesized in myocytes, the lower Cr concentration is likely because of a reduction in Cr-transport protein (57). Although a decline in Cr content in heart failure prevents an increase in ADP concentration (41), a dramatic decline (13,36) could reduce ADP concentration below normal values to the level that reduces CK f lux seen here.…”

Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hementioning

confidence: 73%

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ATP flux through creatine kinase in the normal, stressed, and failing human heart

Weiss

Gerstenblith

Bottomley

2005

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

294

348

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The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is ''energy starved'' has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 ؎ 0.6 vs. 3.2 ؎ 0.9 mol͞g of wet weight per sec, P < 0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and͞or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness.heart failure ͉ magnetic resonance spectroscopy ͉ metabolism A TP provides the chemical energy that fuels myocardial contractile function. Relatively large rates of ATP synthesis are required to sustain normal systolic and diastolic function. The ''energy starvation'' hypothesis of heart failure suggests that inadequate ATP supply underlies the contractile dysfunction present in heart failure (1, 2). Large-scale clinical trials demonstrating that pharmacologic agents such as beta-blockers and angiotensin-converting enzyme inhibitors that reduce metabolic demand improve outcomes in heart failure, whereas those such as positive inotropic agents that increase energetic demand worsen outcomes (3) are consistent with the energy-starvation hypothesis. However, the ability to test the energy-starvation hypothesis has been limited, in part, by an inability to directly measure ATP synthesis in the human heart.Creatine kinase (CK) is central to mammalian energy metabolism and serves as the prime energy reserve of the heart. CK reversibly converts ADP and creatine phosphate (PCr) to ATP and creatine (Cr). This reaction allows tight control of ADP and ATP concentrations in cardiac and skeletal muscle as well as in brain, providing a rapid source of ATP during ischemia and burst activity in skeletal muscle (4-6). It is also hypothesized that the CK reaction serves as an intracellular spatial energy shuttle, facilitating the transfer of high-energy phosphates from the mitochondria (where AT...

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Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hesupporting

confidence: 87%

Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hementioning

confidence: 73%

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Weiss

Gerstenblith

Bottomley

2005

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

294

348

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“…In AK1-deficient hearts, however, the AK response to hypoxia is blunted, creating a significant deficit in energy transfer and reducing the ATP-regeneration potential of the hypoxic myocardium. In this regard, hearts with genetically disrupted AK1 catalysis bear similarities with failing hearts in which the disease-compromised phosphotransfer capacity, including down-regulation in AK as well as CK and glycolytic enzyme activities, precipitates ventricular dysfunction (15,(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress

Pucar

Janssen

Dzeja

et al. 2000

Journal of Biological Chemistry

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Rapid exchange of high energy carrying molecules between intracellular compartments is essential in sustaining cellular energetic homeostasis. Adenylate kinase (AK)-catalyzed transfer of adenine nucleotide ␤-and ␥-phosphoryls has been implicated in intracellular energy communication and nucleotide metabolism. To demonstrate the significance of this reaction in cardiac energetics, phosphotransfer dynamics were determined by [18 O]phosphoryl oxygen analysis using 31 P NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AK activity and ␤-phosphoryl transfer was reduced by 94% and 36%, respectively. This was associated with up-regulation of phosphoryl flux through remaining minor AK isoforms and the glycolytic phosphotransfer enzyme, 3-phosphoglycerate kinase. In the absence of metabolic stress, deletion of AK1 did not translate into gross abnormalities in nucleotide levels, ␥-ATP turnover rate or creatine kinase-catalyzed phosphotransfer. However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased P i /ATP ratio, and suppressed generation of adenosine. Thus, although lack of AK1 phosphotransfer can be compensated in the absence of metabolic challenge, under hypoxia AK1-knockout hearts display compromised energetics and impaired cardioprotective signaling. This study, therefore, provides first direct evidence that AK1 is essential in maintaining myocardial energetic homeostasis, in particular under metabolic stress. Adenylate kinase (AK)1 catalyzes reversible phosphotransfer, 2 ADP 7 AMP ϩ ATP, and participates in de novo synthesis, regeneration and salvage of adenine nucleotides (1-5). AK is particularly abundant in tissues with high energy turnover, where it facilitates transfer of energy-rich ␤-and ␥-phosphoryls and regulates vital ATP-dependent cellular processes (6 -10).In fact, AK may serve as an integral component of phosphotransfer networks, along with creatine kinase (CK) and glycolysis, effectively coupling ATP-generating with ATP-consuming or ATP-sensing intracellular sites (11-15).In the heart, CK-catalyzed phosphotransfer is the major pathway that can transfer high energy phosphoryls derived from the ␥-phosphoryl of ATP (10, 16 -18). Although less active than CK, AK catalysis provides a unique mechanism for transfer and utilization of both ␥-and ␤-phosphoryls in the ATP molecule (10, 15). In this way, AK-catalyzed phosphotransfer doubles the energetic potential of ATP and could provide an additional energetic source under conditions of increased energy demand (10, 19). However, due to lack of membrane permeant and selective AK inhibitors, the biological importance of AK in heart muscle and its role in sustaining myocardial energetics under conditions of metabolic stress have not been established.We have recently demonstrated that deletion of the AK1 gene, which encodes the major AK isoform, produces a phenotype with reduced skelet...

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“…By reducing the mechanical output and pressure after-load, these treatments also indirectly reduce the energy requirements of the failing heart. Whilst the levels of ATP remain at physiological levels during the early stages of HF, there is an observed decrease with the progression towards advanced HF [51]. The reduction in energy supply has been suggested to be related to alterations in substrate utilization, OxPhos and high-energy phosphate metabolism.…”

Section: Heart Failure -End Stagementioning

confidence: 99%

Mitochondria: A mirror into cellular dysfunction in heart disease

White

Edwards

Cordwell

et al. 2008

Proteomics Clinical Apps

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Cardiovascular (CV) disease is the single most significant cause of morbidity and mortality worldwide. The emerging global impact of CV disease means that the goals of early diagnosis and a wider range of treatment options are now increasingly pertinent. As such, there is a greater need to understand the molecular mechanisms involved and potential targets for intervention. Mitochondrial function is important for physiological maintenance of the cell, and when this function is altered, the cell can begin to suffer. Given the broad range and significant impacts of the cellular processes regulated by the mitochondria, it becomes important to understand the roles of the proteins associated with this organelle. Proteomic investigations of the mitochondria are hampered by the intrinsic properties of the organelle, including hydrophobic mitochondrial membranes; high proportion of basic proteins (pI greater than 8.0); and the relative dynamic range issues of the mitochondria. For these reasons, many proteomic studies investigate the mitochondria as a discrete subproteome. Once this has been achieved, the alterations that result in functional changes with CV disease can be observed. Those alterations that lead to changes in mitochondrial function, signaling and morphology, which have significant implications for the cardiomyocyte in the development of CV disease, are discussed.

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Progressive Loss of Myocardial ATP Due to a Loss of Total Purines During the Development of Heart Failure in Dogs

Cited by 166 publications

References 19 publications

ATP flux through creatine kinase in the normal, stressed, and failing human heart

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress

Mitochondria: A mirror into cellular dysfunction in heart disease

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