Published online before print August 6, 2007, doi: 10.1161/CIRCULATIONAHA.107.691253
(Circulation. 2007;116:901-909.)
© 2007 American Heart Association, Inc.
Heart Failure |
Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress
From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Dr Rong Tian, Nuclear Magnetic Resonance Laboratory for Physiological Chemistry, Brigham and Women’s Hospital, 221 Longwood Ave, Room 252, Boston, MA 02115. E-mail rtian{at}rics.bwh.harvard.edu
Received January 19, 2007; accepted June 18, 2007.
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Abstract |
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Background— A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile, but its role in the pathogenesis of cardiac diseases is incompletely understood.
Methods and Results— We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared with wild-type litter mates, the GLUT1-TG mice showed a normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure–volume studies in isolated perfused hearts in the 2-year period. Furthermore, when hearts were subjected to ischemia-reperfusion, cardiac function of young and old GLUT1-TG recovered to the same level (86% and 83%, respectively) and exceeded that of both young and old wild-type hearts (52% and 35%, respectively; P<0.05). Nuclear magnetic resonance spectroscopic measurements with 31P showed delayed ATP depletion, reduced acidosis during ischemia, and improved recovery of high-energy phosphate content in old GLUT1-TG hearts (P<0.05 versus old wild-type). During reperfusion, glucose oxidation was 3-fold higher and fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared with old wild-type (P<0.05), which suggests that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts.
Conclusions— We have demonstrated that a normal heart is able to adapt to long-term increases in basal glucose entry into cardiomyocytes without development of glucotoxicity. Furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.
Key Words: aging • glucose • ischemia • metabolism
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Introduction |
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The heart can utilize multiple classes of energy substrates such as carbohydrates (glucose and lactate), fat (free fatty acids and lipids), and ketones. Although fatty acids serve as the primary energy source in adult hearts, shifts in substrate preference have been observed in a variety of physiological and pathological conditions such as fasting, exercise, aging, diabetes mellitus, myocardial ischemia, and heart failure.1,2 For example, in cardiac hypertrophy and aging, fatty acid oxidation rate decreases in the heart, whereas the relative contribution of glucose increases.3–5 The functional significance of substrate switch under these conditions is poorly understood. We have previously shown that increased insulin-independent glucose transport and utilization in mouse hearts subjected to pressure overload blunted the progression to failure.6 These results suggest that increased reliance on glucose in the hypertrophied heart is adaptive and increased glucose uptake can enhance this compensatory response. In contrast, a large body of literature demonstrates that increased glucose uptake as a consequence of hyperglycemia is detrimental in multiple cell types such as cardiac myocytes, which suggests that substantial increases in glucose uptake may not be desirable.7–11 Thus, we performed a study to assess the life-long effect of increased glucose entry in the heart by use of transgenic mice that overexpress an insulin-independent glucose transporter (GLUT1) in the heart. We found that an increase of myocardial glucose uptake for life did not change the longevity of mice or impair systolic function of the heart but rather prevented the development of diastolic dysfunction in aging hearts. Furthermore, long-term increases in glucose uptake also improved myocardial energetics and rendered the old hearts more resistant to ischemia-reperfusion injury. The present findings provide an important basis for our understanding of substrate metabolism in the heart as well as for pharmacological manipulation of energy metabolism in human diseases.
Editorial p 884
Clinical Perspective p 909
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Methods |
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Animal Models
Transgenic mice that overexpress GLUT1 in the heart (GLUT1-TG) were generated on the FVB background as previously described.6 Age- and gender-matched wild-type (WT) litter mates were used as controls. All mice were kept on a 12-hour light/dark cycle with water and food ad libitum. All procedures related to the handling of the mice in the present study were approved by the Harvard Medical Area Standing Committee on Animals.
Transthoracic Echocardiography
Murine transthoracic echocardiography was conducted in conscious mice at 5- to 6-month intervals with an Acuson Sequoia C-256 echocardiograph machine (Siemens, Malvern, Pa) and a 15-MHz probe.6,12 Briefly, the heart was imaged in the 2-dimensional parasternal short-axis view and an M-mode echocardiogram of the mid-ventricle was recorded at the level of papillary muscles. All mice were imaged by a single operator. Heart rate, posterior and interventricular septum wall thicknesses, and the end-diastolic and end-systolic internal dimensions of the left ventricle (LV) were measured from the M-mode image. On the basis of our prior experience, these measurements were reproduced with an interreader variation <10%. LV wall thickness was assessed as the average of posterior wall and septum thickness. LV fractional shortening was defined as the end-diastolic diameter minus the end-systolic diameter normalized for the end-diastolic diameter; this was used as an index of cardiac contractile function.
Isolated Perfused Heart Experiments and 31P Nuclear Magnetic Resonance Spectroscopy
Mice were heparinized (100 U, intraperitoneally) and anesthetized by sodium pentobarbital (150 mg/kg, intraperitoneally). The heart was excised and perfused at a constant pressure of 80 mm Hg at 37°C as previously described.13 The perfusate contained the following (in mmol/L): NaCl (118), NaHCO3 (25), KCl (5.3), CaCl2 (2), MgSO4 (1.2), EDTA (0.5), glucose (5.5), mixed long-chain fatty acids (0.4, bound to 1% albumin), DL-ß-hydroxybutyrate (0.38), lactate (1.0), and insulin (50 µU/mL); the perfusate was equilibrated with 95% O2 and 5% CO2 (pH 7.4). Hearts were paced at 7.5 Hz throughout the protocol. A water-filled balloon was inserted into the LV to record ventricular pressure and heart rate. After stabilization, a LV pressure–volume (P–V) relationship was obtained by stepwise increases of the balloon volumes until the maximum LV developed pressure was reached for each heart.
In a separate cohort, hearts were subjected to low-flow ischemia (3% of baseline) for 25 minutes and reperfused with 13C-enriched substrates for 45 minutes. Dynamic changes in cardiac high-energy phosphate content and intracellular pH were monitored by 31P nuclear magnetic resonance (NMR) spectroscopy simultaneously with a continuous recording of LV function during ischemia-reperfusion. Coronary effluents were collected before and during ischemia-reperfusion for measurements of lactate output from the heart. At the end of the experiments, hearts were freeze-clamped with Wollenberger tongs that were precooled in liquid nitrogen for 13C-isotopomer analyses.
13C NMR Spectroscopy
Perchloric acid extracts were prepared from freeze-clamped heart tissue, neutralized by KOH, lyophilized, and subsequently dissolved in 300 µL D2O. Proton-decoupled 13C NMR spectra of tissue extracts were obtained with a 3-mm NMR probe on the Varian Inova 400 spectrometer. The contributions of each labeled substrate and the total of the unlabeled exogenous and endogenous substrates to the oxidative metabolism were determined from the peak areas of 13C isotopomers at C3 and C4 of glutamate by modeling of the TCA cycle fluxes as previously described.14–16
Biochemical Measurements and Calibration of 31P NMR Spectra
Cardiac glycogen content was determined by use of an alkaline extraction procedure to separate glycogen and exogenous glucose in the tissue.17 Glucose released from glycogen and lactate content in the coronary effluent were measured with Sigma assay kits (Sigma-Aldrich, St Louis, Mo). Freeze-clamped tissues obtained during baseline perfusion were used for determination of myocardial content of ATP by high-performance liquid chromatography as reported previously.13 Myocardial ATP content measured by high-performance liquid chromatography was converted to ATP with an assumption of an intracellular water content of 0.48 mL/g and a protein content of 0.15 g/g of blotted wet tissue. These values were used to calibrate ATP peak areas in baseline 31P NMR spectra for the respective groups. The average of ß- and 
-ATP peak areas obtained under baseline conditions was set to 100% and used as the reference value for all peaks in all 31P NMR spectra. Intracellular pH was determined by comparison of the chemical shift of inorganic phosphorous and phosphocreatine (PCr) in each spectrum with a standard curve because the chemical shift of inorganic phosphorous but not PCr changes with pH.13
Statistical Analyses
All data are presented as the mean±SEM. One-way ANOVA with Bonferroni post test was performed, and the unpaired t test was used for 2-group comparisons. Two-way repeated measure ANOVA was used to compare the P–V relationships and the responses to ischemia-reperfusion. Survival data were assessed by Kaplan-Meier survival analysis. Analyses were performed with GraphPad Prism (GraphPad Software, San Diego, Calif), and a value of P<0.05 was considered to be significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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General Characteristics of the Mice
To determine the long-term effects of increased glucose uptake in the heart, we followed a cohort of WT (n=42, 48% male) and GLUT1-TG (n=72, 45% male) mice housed in a standard pathogen-free animal facility for up to 2 years. The survival rates of the mice at 22 months were 76% for WT and 72% for GLUT1-TG (Figure 1; P=0.863). Mice 22 to 24 months old were used for the aging studies reported here unless otherwise specified. In young adult mice (5 months), no differences existed in body weight, heart weight, and wet/dry weight ratios for the lung and the liver (Table 1). In old mice (22 to 24 months old), heart weight normalized to tibia length increased by 20% in both WT and GLUT1-TG group. The wet/dry ratio of the lung was slightly but significantly higher in old WT compared with young WT mice (P<0.05), and this difference was not found in GLUT1-TG mice (Table 1).
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Cardiac Function of Old GLUT1-TG Mice
We tracked cardiac function of the GLUT1-TG mice by echocardiography in conscious mice every 5 to 6 months during the 2-year period. As shown in Figure 2, an age-dependent increase in LV wall thickness and LV internal diameter existed for both WT and GLUT1-TG hearts, consistent with the increase in heart weight shown above. The LV fractional shortening was sustained up to 18 months and declined modestly at 2 years for both genotypes. No difference was observed between WT and GLUT1-TG mice at any age point.
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To determine myocardial contractile function independent of neurohormonal regulation, we assessed LV P–V relationships in isolated perfused hearts. Compared with young hearts (4 months old), the peak LV developed pressure in old hearts (22 months old) was decreased in both genotypes (Figure 3; P<0.05), which suggests an age-associated decline in systolic function. When WT and GLUT1-TG hearts were compared at each age point, the P–V relationships as well as the peak LV developed pressures were similar at 4 months (110±9 (WT) versus 120±7 mm Hg (GLUT1-TG); P=0.333) as well as at 22 months (72±5 (WT) versus 86±5 mm Hg (GLUT1-TG); P=0.09). The P–V relationship for end-diastolic pressure was indistinguishable for WT and GLUT1-TG hearts at 4 months of age (Figure 3A). At 22 months, the relationship shifted upward and leftward in WT compared with GLUT1-TG (Figure 3, B and C; P=0.019x2-way repeated measure ANOVA), which suggests an impaired diastolic function in old WT but not in old GLUT1-TG hearts. This finding was consistent with the modest increase of water content found only in the lung of old WT mice.
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Responses of Old GLUT1-TG Hearts to Ischemia
To determine the long-term effects of increased glucose uptake on responses to ischemic injury in old hearts, we assessed cardiac function in young and old GLUT1-TG hearts subjected to 25 minutes of low-flow ischemia (3% of baseline coronary flow) and 45 minutes reperfusion. Compared with age-matched WT hearts, the GLUT1-TG hearts showed less diastolic contracture during ischemia and a greater recovery of LV end-diastolic pressure during reperfusion (Figure 4A). In WT group, impairment of diastolic function was worsened in old hearts consistent with the notion that aging hearts are more susceptible to ischemic insults. However, age-associated diastolic dysfunction was attenuated in GLUT1-TG hearts during reperfusion, the diastolic pressure returned to pre-ischemic level in both young and old hearts after reperfusion (Figure 4). Similarly, the recovery of LV developed pressure at the end of reperfusion reached 86% and 83% of the preischemic level in young and old GLUT1-TG hearts, respectively (P was nonsignificant) compared with that of 52% and 35% in young and old WT hearts, respectively (Figure 4B, P<0.05). The coronary flow rate was similar during ischemia for WT and GLUT1-TG hearts (
0.07 mL/min), and the recovery at the end of reperfusion was not different among the groups (Figure 4C). Together, these results suggested that the tolerance to ischemia-reperfusion injury was markedly improved in old GLUT1-TG hearts, and age-associated deterioration was reduced in GLUT1-TG.
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To determine whether the functional improvement in old GLUT1-TG hearts can be attributed to preserved myocardial energetic status, we measured dynamic changes of high-energy phosphate content in the heart. Before ischemia, ATP was similar in all groups. The concentration of PCr, the energy reserve compound, was lower in old WT hearts but was sustained in old GLUT1-TG hearts (Figure 5A, P<0.05). Although PCr decreased rapidly during ischemia, the rate of ATP depletion was significantly blunted in GLUT1-TG hearts (Figure 5B). ATP was >2-fold higher in GLUT1-TG compared with age-matched WT at the end of ischemia. By the end of reperfusion, ATP in old GLUT1-TG was 3 times higher than old WT hearts and exceeded the level of young WT hearts. Of note, a smaller decline of intracellular pH occurred in old GLUT1-TG hearts during ischemia (Figure 5C, P<0.05) despite the assumption that increased glycolysis in these hearts would aggravate acidosis. Thus, these results suggested that improved energy supply in old GLUT1-TG hearts during ischemia was associated with preserved myocardial energetics and fewer disturbances of ion homeostasis.
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To determine the role of substrate metabolism in the postischemic recovery of myocardial energetics and contractile function, we assessed net changes in glycogen content, glycolytic activity, and substrate oxidation in hearts during ischemia and reperfusion. The lactate output from old GLUT1-TG hearts during normal perfusion was 5-fold higher than age-matched WT hearts (Figure 6A), consistent with our prior observations in young GLUT1-TG hearts.6 During the low-flow ischemia, lactate output was low in all groups, whereas a large amount of lactate was detected in the coronary effluent in the first 5 minutes of reperfusion (Figure 6A). These results suggested that the low flow rate during ischemia was not sufficient to wash out lactate from the heart in either group. Thus, lactate washout during the first 5 minutes of reperfusion was included in the estimation of total amount of lactate produced during ischemia. Cardiac glycogen content at baseline, at the end of ischemia, and at the end of reperfusion was shown in Table 2, and the net glycogen depletion during ischemia was compared with the total lactate output during ischemia. Glycogen content was higher in GLUT1-TG hearts before ischemia, but the net glycogen depletion during ischemia was similar in WT and GLUT1-TG hearts. Even if 100% of net glycogenolysis contributed to anaerobic glycolysis, it would account for 39% and 35% of total lactate output in WT and GLUT1-TG hearts during ischemia, respectively. Thus, increased glucose uptake rather than higher glycogen content likely accounted for increased glycolysis in GLUT1-TG hearts.
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The substrate oxidation profile was determined during reperfusion period with 13C NMR isotopomer analysis (Figure 6B). Similar to previous observations in adult hearts, the contribution of fatty acids to oxidative metabolism predominates during reperfusion. However, the contribution of glucose was increased by 2- and 3-fold in young and old GLUT1-TG hearts compared with age-matched WT. Moreover, the relative contribution of fatty acid oxidation was markedly reduced in old GLUT1-TG hearts (decreased by 45% versus old WT). Thus, glucose and fatty acids contribute to the similar extents in old GLUT1-TG hearts during reperfusion. Interestingly, enhanced oxidation of glucose over fatty acids was associated with marked improvement of energetic and functional recovery in the old transgenic hearts even though the rate of lactate output remained higher in the old GLUT1-TG hearts during reperfusion compared with old WT hearts; thus a significant fraction of glycolytic flux remained uncoupled from oxidation.
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Discussion |
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The present study demonstrates that life-long increases of continuous basal glucose uptake (insulin-independent) in the mouse heart do not adversely alter cardiac morphology, contractile function, or survival during the 2-year period. Instead, we have found evidence of improved diastolic function in mouse hearts with long-term increases in glucose uptake during normal aging. Furthermore, long-term increases in glucose uptake and utilization have preserved myocardial energetics and attenuated aging-caused susceptibility to ischemia-reperfusion in mouse hearts. These observations strongly suggest that the heart is able to adapt to sustained high rates of glucose transport into cardiac myocytes and that long-term increases in intracellular glucose by themselves cause no long-term adverse consequences.
It is generally recognized that the adult heart utilizes fatty acids as the primary energy substrate, whereas the fetal heart mainly relies on carbohydrates (glucose and lactate). Recent studies of energy metabolism in cardiac hypertrophy and failure suggest that the substrate preference in failing hearts is shifted toward glucose, manifested as increased glucose uptake and glycolysis compared with normal hearts when supplied with identical compositions of carbohydrates and fatty acids.3,18 Such a change is noted as a reversion to fetal metabolic profile by many, and it remains unclear whether it is adaptive or maladaptive. Prior studies of cardiac myocytes exposed to high levels of glucose have demonstrated contractile dysfunction and cell death that are dependent on the increases in intracellular glucose, which suggests that increased glucose entry causes glucotoxicity.7,8,10,11 In the present study, we use a transgenic mouse model in which myocardial glucose uptake rates are 40-fold higher in the absence of insulin and 2-fold higher than maximum insulin-stimulated glucose uptake in WT.6 Despite the substantially elevated glucose entry, the cardiac morphology and function are not different from normal WT mice during the 2-year period. We have also shown that these hearts adapt to increased glucose influx by alteration of the expressions of proteins involved in glucose and fatty acids metabolism, which results in increased glycolysis and glucose oxidation and decreased contribution of noncarbohydrates such as fatty acids and ketones to the oxidative metabolism.16,19,20 Thus, although increased myocardial glucose uptake and a greater reliance on glucose present as reappearance of fetal metabolic profile, the normal heart is able to adapt to such a metabolic pattern for life. Moreover, increased glucose uptake and utilization has been found to be beneficial for hypertrophied and failing hearts and in hearts with impaired fatty acid oxidation.6,16,21
It has been suggested that exposure of cardiac myocytes to high-glucose media resulted in impaired E-C coupling and prolonged relaxation that was dependent on increased glucose entry and metabolism.10,22 In addition, we have previously shown that impaired cell relengthening in senescent mouse cardiac myocytes was a mechanism for diastolic dysfunction in aging hearts.23 Thus, we investigated whether long-term increases in glucose uptake had a negative impact on diastolic function during aging in GLUT1-TG hearts. Interestingly, we have shown that the diastolic P–V relationship is preserved in old GLUT1-TG hearts compared with age-matched WT hearts. We speculate that the differences in the present observations made in mouse hearts compared with the previous findings in cardiac myocytes cultured in high-glucose media are the result of the nonbeating nature of cultured myocytes, which renders the metabolic rate markedly lower than a beating heart, and hence we caution the interpretation of metabolic studies that use quiescent cardiac myocytes.
Previous studies by others and us have shown that glucose supply plays a critical role in cardiac responses to ischemia and increased glucose delivery during acute ischemia is cardioprotective.24–26 Results from the present study suggest that long-term increases in glucose delivery to the heart do not alter function of normal hearts but improve tolerance to ischemic stress, and these benefits are independent of changes in signaling mechanisms involved in cardioprotection such as Akt and AMPK (online-only Data Supplement). Importantly, we show that long-term increases in glucose uptake reduce aging-associated increases of susceptibility to ischemia-reperfusion insult. Old GLUT1-TG hearts are not only protected from ischemia-reperfusion injury compared with age-matched WT hearts, but old GLUT1-TG hearts also recovered to the similar level as young GLUT1-TG hearts during reperfusion. This is consistent with previous reports that showed that aged hearts develop increased dependence on glucose and glycogen and yet have reduced ability to upregulate glucose utilization during stresses.27–29
Several differences in energy metabolism observed in the present study likely contribute to the improved tolerance to ischemia-reperfusion injury in old transgenic hearts. First, a greater level of the energy reserve compound PCr is present in old transgenic hearts. It has been shown that aging is associated with a decline of PCr content in the heart.30,31 Consistently, we found that PCr was lower in old WT hearts but was maintained at normal adult levels in old transgenic hearts. PCr serves as an energy reserve by a rapid transfer of its high-energy phosphoryl group to ATP at the onset of ischemia to temporarily offset the depletion of ATP. Sustained energy reserve in old transgenic hearts results in a significant, albeit brief, delay in the depletion of ATP during the first 4 minutes of ischemia. The favorable energy status is maintained by a robust glycolytic ATP production in the old transgenic hearts fueled by a greater rate of glucose uptake. Although it has been repeatedly shown that increased glycolytic ATP synthesis is protective during ischemia,24,26,27,32 concerns have been raised that excessive anaerobic glycolysis may exacerbate intracellular acidosis and hence worsen ischemic injury.33–35 It has been speculated that the benefit of enhanced glycolysis during low-flow ischemia found in perfused hearts ex vivo could be biased as a result of the washout of lactate by a relatively high coronary flow rate. In the present study, at a flow rate of 0.07 mL/min during ischemia, lactate washout was incomplete in both WT and transgenic hearts. Despite the fact that a smaller fraction of lactate was washed out in old transgenic hearts, less acidosis was present in these hearts versus WT hearts. These results suggest that proton homeostasis is better maintained in old transgenic hearts. Because we observed no active contractile activity in any of the hearts during ischemia, we speculate that improved ATP supply in the old transgenic hearts is most likely used for the maintenance of ion pump function and hence minimizes myocardial injury.
It has been well recognized that excessive fatty acid oxidation during reperfusion plays an important role in myocardial damage. Increased fatty acid oxidation during reperfusion leads to impaired glucose oxidation and uncouples glycolytic flux from oxidative metabolism, which thus increases proton load and decreases cardiac efficiency.33–35 Thus, an increase in glycolytic flux under such conditions would be undesirable. Interestingly, we found improved functional recovery in young GLUT1-TG was associated with high rates of fatty acid oxidation even though glucose oxidation also doubled. It is possible that the greater functional recovery primarily reflects improved ischemic tolerance in this group. Nevertheless, we found that old transgenic hearts were able to sustain enhanced glucose oxidation over fatty acid oxidation during reperfusion and demonstrated an improved postischemic recovery in both energetics and function. Taken together, these results suggest that a normal heart is not only able to adapt to long-term increases of intracellular glucose but also develops a metabolic phenotype that is more tolerant to ischemic insult in old age.
Finally, it is important to recognize the limitations of studies that use transgenic mouse models such as the present model. Increased glucose uptake is initiated in the present mouse model at birth. It is possible that adaptations developed during maturation contribute to the phenotype of uncompromised cardiac function despite life-long increases in intracellular glucose. The nature of these adaptations that developed and importantly whether adult-onset of increased glucose supply also triggers similar responses are not addressed by the present study but should be pursued in future studies that use a modified model such as conditional transgenic mice. Moreover, the present proof-of-concept study is performed in otherwise healthy mice. Although such an approach allows us to dissect the functional consequence of a single metabolic alteration, additional studies are clearly necessary to integrate these results into complex disease conditions. We have previously shown that increased glucose uptake restores contractile reserve in hearts with impaired fatty acid oxidation, and that GLUT1-TG hearts are protected from the development of heart failure by chronic pressure overload, another condition of reduced capacity for fatty acid oxidation.6,16 The consequence of increased myocardial glucose uptake in hearts with high rates of fatty acid oxidation such as diabetes mellitus and obesity remains to be tested.
In summary, we have demonstrated that a normal heart is able to adapt to long-term increases in insulin-independent glucose entry into cardiomyocytes and that life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against increased sensitivity to ischemic injury in old hearts. Observations made in the present study provide an important basis for future studies to address the role of altered energy substrate preference in complex disease conditions as well as to identify novel mechanisms for metabolic therapy of heart disease.
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Acknowledgments |
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Sources of Funding
The present work was supported by research grants HL071775 (to Dr Liao), and HL059246, AG000837, HL067970, and HL088634 (to Dr Tian) from the National Institutes of Health. Dr Luptak was supported by a postdoctoral fellowship from the American Heart Association Northeast Affiliate. Dr Tian is an Established Investigator for the American Heart Association.
Disclosures
None.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994; 1213: 263–276.[Medline] [Order article via Infotrieve]
2. Opie LH. The Heart: Physiology, From Cell to Circulation. 3rd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1998.
3. Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk GD. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol. 1994; 267: H742–H750.[Medline] [Order article via Infotrieve]
4. Barger PM, Kelly DP. Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci. 1999; 318: 36–42.[CrossRef][Medline] [Order article via Infotrieve]
5. Kates AM, Herrero P, Dence C, Soto P, Srinivasan M, Delano DG, Ehsani A, Gropler RJ. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol. 2003; 41: 293–299.
6. Liao R, Jain M, Cui L, D’Agostino J, Aiello F, Luptak I, Ngoy S, Mortensen RM, Tian R. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation. 2002; 106: 2125–2131.
7. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002; 51: 1938–1948.
8. Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 2001; 50: 2363–2375.
9. Modesti A, Bertolozzi I, Gamberi T, Marchetta M, Lumachi C, Coppo M, Moroni F, Toscano T, Lucchese G, Gensini GF, Modesti PA. Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress. Diabetes. 2005; 54: 394–401.
10. Ren J, Gintant GA, Miller RE, Davidoff AJ. High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner. Am J Physiol. 1997; 273: H2876–H2883.[Medline] [Order article via Infotrieve]
11. Shizukuda Y, Reyland ME, Buttrick PM. Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes. Am J Physiol Heart Circ Physiol. 2002; 282: H1625–H1634.
12. Jain M, Lim CC, Nagata K, Davis VM, Milstone DS, Liao R, Mortensen RM. Targeted inactivation of Galpha(i) does not alter cardiac function or beta-adrenergic sensitivity. Am J Physiol Heart Circ Physiol. 2001; 280: H569–H575.
13. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, Goodyear LJ, Tian R. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha 2 subunit of AMP-activated protein kinase. J Biol Chem. 2003; 278: 28372–28377.
14. Malloy CR, Sherry AD, Jeffrey FM. Analysis of tricarboxylic acid cycle of the heart using 13C isotope isomers. Am J Physiol. 1990; 259: H987–H995.[Medline] [Order article via Infotrieve]
15. Malloy CR, Sherry AD, Jeffrey FM. Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy. J Biol Chem. 1988; 263: 6964–6971.
16. Luptak I, Balschi JA, Xing Y, Leone TC, Kelly DP, Tian R. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation. 2005; 112: 2339–2346.
17. Passonneau JV, Lauderdale VR. A comparison of three methods of glycogen measurement in tissues. Anal Biochem. 1974; 60: 405–412.[CrossRef][Medline] [Order article via Infotrieve]
18. Tian R, Musi N, D’Agostino J, Hirshman MF, Goodyear LJ. Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation. 2001; 104: 1664–1669.
19. Yan J, Cui L, Luptak I, Liao R, Tian R. Increasing glucose entry downregulates peroxisome Pproliferator-activated receptor alpha expression in the heart. Circulation. 2005; 112: II-284. Abstract.
20. Yan J, Young ME, Lopaschuk GD, Liao R, Tian R Substrate availability regulates energy metabolism via transcriptional mechanisms. Circulation. 2006; 114: II-135. Abstract.
21. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004; 110: 955–961.
22. Davidoff AJ, Ren J. Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes. Am J Physiol. 1997; 272: H159–H167.[Medline] [Order article via Infotrieve]
23. Lim CC, Apstein CS, Colucci WS, Liao R. Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte. J Mol Cell Cardiol. 2000; 32: 2075–2082.[CrossRef][Medline] [Order article via Infotrieve]
24. Cave AC, Ingwall JS, Friedrich J, Liao R, Saupe KW, Apstein CS, Eberli FR. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation. 2000; 101: 2090–2096.
25. King LM, Opie LH. Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow. Cardiovasc Res. 1998; 39: 381–392.
26. Tian R, Abel ED. Responses of GLUT4-deficient hearts to ischemia underscore the importance of glycolysis. Circulation. 2001; 103: 2961–2966.
27. Boucher F, Tanguy S, Toufektsian MC, Besse S, de Leiris J. Effects of fasting and exogenous glucose delivery on cardiac tolerance to low-flow ischemia in adult and senescent rats. Mech Ageing Dev. 2000; 116: 15–32.[CrossRef][Medline] [Order article via Infotrieve]
28. Soto PF, Herrero P, Kates AM, Dence CS, Ehsani AA, Davila-Roman V, Schechtman KB, Gropler RJ. Impact of aging on myocardial metabolic response to dobutamine. Am J Physiol Heart Circ Physiol. 2003; 285: H2158–H2164.
29. Yan L, Ge H, Li H, Lieber SC, Natividad F, Resuello RR, Kim SJ, Akeju S, Sun A, Loo K, Peppas AP, Rossi F, Lewandowski ED, Thomas AP, Vatner SF, Vatner DE. Gender-specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts. J Mol Cell Cardiol. 2004; 37: 921–929.[CrossRef][Medline] [Order article via Infotrieve]
30. Bak MI, Wei JY, Ingwall JS. Interaction of hypoxia and aging in the heart: analysis of high energy phosphate content. J Mol Cell Cardiol. 1998; 30: 661–672.[CrossRef][Medline] [Order article via Infotrieve]
31. Schocke MF, Metzler B, Wolf C, Steinboeck P, Kremser C, Pachinger O, Jaschke W, Lukas P. Impact of aging on cardiac high-energy phosphate metabolism determined by phosphorus-31 2-dimensional chemical shift imaging (31P 2D CSI). Magn Reson Imaging. 2003; 21: 553–559.[CrossRef][Medline] [Order article via Infotrieve]
32. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004; 114: 495–503.[CrossRef][Medline] [Order article via Infotrieve]
33. Dyck JR, Lopaschuk GD. Glucose metabolism, H+ production and Na+/H+-exchanger mRNA levels in ischemic hearts from diabetic rats. Mol Cell Biochem. 1998; 180: 85–93.[CrossRef][Medline] [Order article via Infotrieve]
34. Liu B, Clanachan AS, Schulz R, Lopaschuk GD. Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res. 1996; 79: 940–948.
35. Liu Q, Docherty JC, Rendell JC, Clanachan AS, Lopaschuk GD. High levels of fatty acids delay the recovery of intracellular pH and cardiac efficiency in post-ischemic hearts by inhibiting glucose oxidation. J Am Coll Cardiol. 2002; 39: 718–725.
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Footnotes |
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Guest Editor for this article was Lionel Opie, MD.
*The first 2 authors contributed equally to this work. 
The online-only Data Supplement, consisting of a figure, is available online with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.691253/DC1.
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