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activation required for decreased glucose uptake and increased susceptibility to injury during ischemia
1University Laboratory of Physiology, University of Oxford, and 2Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom
Submitted 8 March 2004 ; accepted in final form 11 January 2005
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ABSTRACT |
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(PPAR-) in modulating cardiac insulin-sensitive glucose transporter (GLUT-4) protein levels in altered metabolic states and to determine the functional consequences by assessing cardiac ischemic tolerance. Wild-type and PPAR--null mouse hearts were isolated and perfused 6 wk after streptozotocin administration or after 14 mo on a high-fat diet or after a 24-h fast. Myocardial D-[2-3H]glucose uptake was measured during low-flow ischemia, and differences in GLUT-4 protein levels were quantified using Western blotting. In wild-type mice in all three metabolic states, elevated plasma free fatty acids were associated with lower total cardiac GLUT-4 protein levels and decreased glucose uptake during ischemia, resulting in poor postischemic functional recovery. Although PPAR--null mice also had elevated plasma free fatty acids, they had neither decreased cardiac GLUT-4 levels nor decreased glucose uptake during ischemia and, consequently, did not have poor recovery during reperfusion. We conclude that elevated plasma free fatty acids are associated with increased injury during ischemia due to decreased cardiac glucose uptake resulting from lower cardiac GLUT-4 protein levels, the levels of GLUT-4 being regulated, probably indirectly, through PPAR- activation.
diabetic mouse heart; GLUT-4
-oxidation, for which a major regulator is the peroxisome proliferator-activated receptor- (PPAR-), a member of the ligand-activated nuclear receptor superfamily (3, 15, 34). Among the ligand activators of PPAR- are long-chain fatty acids, in that increased uptake of fatty acid substrate into the heart induces a transcriptional response leading to increased expression of fatty acid -oxidation enzymes (6, 15, 34).
In the PPAR--null mouse, the capacity for myocardial -oxidation of long-chain fatty acids is markedly reduced, because fatty acid-metabolizing enzymes are expressed at much lower levels than in the wild-type mouse (2, 6, 34). Not only are rates of palmitate oxidation lower, but rates of glucose oxidation and glycolysis are increased (6), to the extent that hearts from PPAR--null mice are able to maintain normal function in the unstressed state but fail to increase work with inotropic challenge and develop cardiomyopathy with aging (34). A fasting stress, which in wild-type mice induces cardiac -oxidation enzyme gene expression, causes cardiac and hepatic triglyceride accumulation and high plasma levels of free fatty acids, hypoketonemia, hypoglycemia, and hypothermia (15, 17, 20, 22, 29).
In the heart, much of the ATP necessary for contractile function is provided by fatty acid oxidation (21). In the uncontrolled diabetic state, because of the combined effects of high circulating free fatty acids and decreased glucose uptake across the sarcolemma, the heart uses fats almost exclusively to support ATP synthesis (1, 4, 7, 23, 25, 28, 33). Increased fatty acid oxidation occurs at the expense of glucose metabolism, which increases the vulnerability of the heart to damage during ischemic insults (8, 19). Glycolytic ATP, as opposed to ATP derived from oxidative phosphorylation, is important for ischemic cell viability by maintaining Na+-K+-ATPase (9) and sarcoplasmic reticulum Ca2+-ATPase activities (35). Glucose transport and glycolytic rates determine the extent of ischemic injury (18, 27), with cardiac-specific GLUT-4 glucose transporter protein knockout mice having decreased glucose uptake and increased ischemic injury (30).
Marked reductions in cardiac GLUT-4 levels have been observed in insulin-resistant states, such as Type 2 diabetes, and in insulin-deficient states, such as fasting and after streptozotocin (STZ) treatment (11, 12, 27). In the cardiac-specific PPAR--overexpressing mouse, the expression of genes involved in cardiac fatty acid uptake and oxidation was increased, whereas the expression of genes involved in glucose transport (GLUT-4, but not GLUT-1) and utilization was repressed, a metabolic phenotype similar to that of the diabetic heart (14). Thus alterations in normal cardiac glucose metabolism may occur via modulation of PPAR- expression. The aim of this study was to determine whether the cardiac metabolic effects associated with diabetes (28) occur via PPAR-, particularly with respect to glucose uptake and susceptibility to ischemic injury.
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METHODS |
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-null mice were a generous gift of Frank J. Gonzalez (National Cancer Institute, Bethesda, MD). All mice were housed on a 12:12-h light-dark cycle (lights on 7 AM and lights off at 7 PM) in animal facilities at the University of Oxford. All animal studies were performed between 8 AM and 2 PM, during their early absorptive (fed) state, unless otherwise stated. All procedures were approved by the University of Oxford Animal Ethics Review Committees and by the Home Office (London, UK).
STZ-induced diabetes.
A cumulative dose of 210 mg/kg mouse body wt of STZ (Sigma, St. Louis, MO) dissolved in 50 mmol/l citrate (pH 4.5) was used to induce Type 1 diabetes in 6-mo-old male wild-type SVEV129 and PPAR--null mice. STZ was administered in three daily injections of 85, 70, and 55 mg/kg ip (23). Wild-type mice were injected with vehicle. All STZ-injected mice were given a 10% glucose solution to drink for 24 h, after which their urine was tested for glucose using glucose sticks (Clinistix, Ames, Slough, UK). Only STZ-injected mice demonstrating significantly elevated urine glucose, 
95% of mice injected, were studied 6 wk after the injection.
High fat feeding.
Male SVEV129 wild-type and PPAR--null mice were fed ad libitum a standard chow diet (5% fat, 23.5% protein, and 49% carbohydrate) or a "high-fat" diet (30% fat, 23.5% protein, and 24% carbohydrate; Special Diet Services), in which fat replaced the carbohydrate in the standard chow. High fat feeding commenced at 4–5 wk of age and continued until 15 mo of age, at which time the mice were studied.
Twenty-four-hour fast.
Six-month-old male wild-type SVEV129 and PPAR--null mice were fasted for 24 h before the start of the experiment. The mice had free access to water at all times during the fast. After 24 h, a rectal temperature probe attached to a thermocoupler (model KM 330, Kane May Universal, Hertfordshire, UK) was used to measure body temperature in anesthetized mice.
Blood metabolites. Mice were anesthetized with a 0.1-ml injection of pentobarbitone sodium (60 mg/ml ip; Sagatal, Rhône Mèrieux, Dublin, Ireland), and experiments were performed after the loss of corneal and pedal reflexes. A syringe rinsed with heparin solution was used to draw 300 µl of blood from the chest cavity after the heart was excised. Blood was immediately centrifuged (3,000 rpm for 10 min at 4°C), and plasma was removed. The lipoprotein lipase inhibitor tetrahydrolipstatin was added (2.5 µl of 0.6 mg/ml tetrahydrolipstatin) to 50-µl plasma samples aliquoted for nonesterified fatty acid (NEFA) analysis. All plasma samples were immediately frozen and stored at –80°C. Plasma glucose was measured using an assay kit (Randox Laboratories, Antrim, UK), and free fatty acids were measured using the NEFA C kit (Wako Chemicals, Neuss, Germany). Plasma total cholesterol was measured using an assay kit (Randox Laboratories), as was plasma triacylglycerol (Bio-Stat Diagnostic Systems, Stockport, UK). Plasma insulin was measured using the mouse insulin ELISA (Mercodia, Uppsala, Sweden).
Ischemia and reperfusion. Mice were anesthetized with a 0.1-ml injection of pentobarbitone sodium (60 mg/ml ip). After cessation of peripheral nervous function, hearts were quickly excised and arrested in heparin-containing Krebs-Henseleit (KH) buffer. The hearts were trimmed of excess tissue, washed, and weighed. Hearts were cannulated via the ascending aorta for retrograde Langendorff perfusion at 37°C using modified KH buffer containing (in mM) 118 NaCl, 4.7 KCl, 1.2 MgSO4, 2.25 CaCl2, 25 NaHCO3, 0.5 EDTA, 11 glucose, 4.5 pyruvate, and 0.5 lactate (19). The buffers were continually gassed with 95% O2-5% CO2. A volume of 150 ml of buffer was recirculated and continuously filtered using an in-line prefilter, followed by 0.8- and 0.45-µm filters (Millipore, Bedford, MA).
A water-filled polyethylene balloon, attached via polyethylene tubing to a Gould pressure transducer (model P23 dB), was inserted into the left ventricular (LV) cavity via the mitral valve and inflated sufficiently to produce an end-diastolic pressure of 4–7 mmHg. Heart rate and LV pressures were recorded continuously using a BIOPAC MP30 system (BIOPAC Systems) attached to a personal computer running the BSL Pro 3.6.7 program (BIOPAC Systems). LV developed pressure was calculated as the systolic pressure minus the end-diastolic pressure. The rate-pressure product was the product of the developed pressure and the heart rate.
All hearts were perfused at a constant flow of 12 ml·g wet wt–1·min–1 for 30 min before 40 min of ischemia at 0.5 ml·g wet wt–1·min–1. During ischemia, lactate and pyruvate were omitted from the perfusion buffer, and D-[2-3H]glucose was added to measure glucose uptake. Hearts were then reperfused for 30 min under the same conditions as during preischemia (see above). After reperfusion, hearts were freeze clamped and stored at –80°C.
Glucose uptake during ischemia. Glucose uptake was measured using D-[2-3H]glucose, as described previously (19, 27). At 7 min before ischemia, the perfusate was switched to recirculating KH buffer containing 11 mmol/l glucose and D-[2-3H]glucose with an activity of 14.5 µCi/ml (Amersham, Bucks, UK). Buffer samples (0.4 ml) were taken immediately before and after ischemia to establish baseline counts, and effluent from the heart was collected over consecutive 4-min intervals during low-flow ischemia. Each effluent sample (200 µl) was run through a glass column containing Dowex 1 x 8-200 resin previously washed with 2 N Na+-borate (50 g/l NaOH and 100 g/l boric acid) to pH 7. The effluent was collected from the glass columns in scintillation vials containing 10 ml of Ecolite scintillation fluid. The columns were washed with 2 ml of water, which was also collected into the vials. For the calculation of D-[2-3H]glucose specific radioactivity in the buffer, 200 µl of effluent from samples taken at the start and end of ischemia were added to vials with 2 ml of water and 10 ml of Ecolite. All the vials were then vortexed thoroughly and counted for 4 min using a Beckman liquid scintillation counter.
Glucose transporter protein expression.
Frozen cardiac tissue was homogenized in lysis buffer containing 75 mmol/l Tris (pH 6.8), 3.8% SDS, 4 M urea, and 20% glycerol. The homogenates were boiled at 98–100°C for 5 min and centrifuged at 13,000 rpm for 5 min to remove nonlysed tissue. Protein concentrations of the supernatants were determined using an assay kit and bovine serum albumin as a standard. After the addition of 5% -mercaptoethanol, the samples were boiled for 5 min at 95°C and stored at –80°C.
For direct immunoblotting studies, equal amounts of solubilized protein (3 µg) were resuspended in Laemmli sample buffer containing 20 mmol/l DTT and separated by 10% SDS-PAGE. The resolved proteins were electrophoretically transferred to nitrocellulose membranes using a transfer buffer containing 48 mmol/l Tris, 39 mmol/l glycine, 0.0375% SDS, and 20% methanol (pH 8.8) and a semidry transfer apparatus (Bio-Rad, Hercules, CA). The nitrocellulose membranes were incubated in Tris-buffered saline-Tween 20 (0.9% NaCl, 10 mmol/l Tris, and 0.1% Tween 20) supplemented with 5% milk to reduce nonspecific binding and incubated for 2 h at room temperature with a 1:4,000 dilution of anti-COOH-terminal GLUT-4 antibody (rabbit serum; Geoffrey Holman, University of Bath, Bath, UK). After the addition of the secondary antibody, a 1:2,000 dilution of goat anti-rabbit IgG-horseradish peroxidase (Santa Cruz Biotechnology, Santa Cruz, CA), the signal was detected by ECL Plus (Amersham Biosciences, Little Chalfont, UK) and quantified by densitometry using Qscan 32 image analysis software (Biosoft).
Statistical analysis. Values are means ± SE. Statistical significance was assessed using a one-way analysis of variance with post hoc t-test with Bonferroni’s correction where appropriate. Differences were considered significant at P < 0.05.
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RESULTS |
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-null mice. There were no differences in heart weights or heart weight-to-body weight ratios between any of the groups (Table 1). Injection with STZ led to similar changes in plasma metabolite and insulin concentrations in the wild-type and PPAR--null mice: >2-fold increase in plasma glucose, 50% decrease in plasma insulin, 2-fold increase in plasma free fatty acids, 1.7-fold increase in triacylglycerol, and 1.3-fold increase in total cholesterol compared with vehicle-injected mice (Table 1).
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-null mice had normal function (Table 1). On reperfusion, hearts from STZ-injected wild-type mice had 32% lower LV developed pressures and 43% lower rate-pressure products than vehicle-injected wild-type mice (Table 1). The lower recovery after ischemia was not observed in STZ-injected PPAR--null mice (Table 1).
Hearts from STZ-injected wild-type mice took up 44% less glucose during ischemia than hearts from vehicle-injected wild-type mice: 9.0 ± 2.1 vs. 16.8 ± 1.2 µmol/g wet wt (Fig. 1A). STZ injection did not alter cardiac glucose uptake in PPAR--null mice. A representative immunoblot for GLUT-4 is shown in Fig. 1, which also shows 37% lower GLUT-4 protein levels in hearts from wild-type mice injected with STZ than in wild-type mice injected with vehicle (Fig. 1, B and C). Hearts from STZ-injected PPAR--null mice had no decrease in cardiac GLUT-4 protein levels compared with hearts from vehicle-injected mice (Fig. 1, B and C).
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on the heart during high fat feeding. At 15 mo of age, after 14 mo on a high-fat diet, all fat-fed mice had 1.5-fold greater body weights, and, because the heart weights did not increase, the heart weight-to-body weight ratios decreased by 27% compared with mice fed a standard diet (Table 2). Plasma glucose was elevated 1.6-fold and plasma insulin was raised 4.1-fold only in wild-type mice fed a high-fat diet and not in PPAR--null mice fed a high-fat diet (Table 2). In all mice fed a high-fat diet, plasma free fatty acids were significantly elevated 3.0-fold, with the levels significantly higher in the PPAR--null mice: 1.7-fold elevation in plasma triacylglycerol and 1.4-fold increase in plasma cholesterol compared with mice fed a standard diet.
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-null mice fed a high-fat diet recovered to the same extent as hearts from PPAR--null mice fed a standard diet.
Hearts from wild-type mice fed a high-fat diet took up 35% less glucose during ischemia than those from wild-type mice fed a standard diet: 10.4 ± 1.9 vs. 16.7 ± 1.0 µmol/g wet wt (Fig. 2A). There was no difference in cardiac glucose uptake between PPAR--null mice fed a high-fat diet and mice fed a normal diet. A representative immunoblot for GLUT-4 is shown in Fig. 2B. GLUT-4 protein was 43% lower in hearts from wild-type mice fed a high-fat diet than in hearts from wild-type mice fed a standard diet, but GLUT-4 levels were normal in all hearts from PPAR--null mice, irrespective of diet (Fig. 2, B and C).
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occur in the short term (24 h). Fasted wild-type mice were able to maintain their body temperature, but fasted PPAR--null mice showed a 6–7°C decrease in body temperature compared with all other mice (Table 3). Plasma glucose concentrations were 74% lower in fasted PPAR--null mice than in all other mice, and plasma insulin was 70% lower in all fasted mice than in the fed mice (Table 3). Plasma free fatty acid concentrations were significantly greater in wild-type fasted mice than in wild-type fed mice. In PPAR--null mice, plasma free fatty acid concentrations were 2.7-fold higher after fasting. Plasma triacylglycerol was reduced by 50% in all fasted mice compared with all fed mice (Table 3).
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-null mice had the same recovery of function during reperfusion.
Wild-type hearts from fasted mice took up 28% less glucose during the ischemic period than wild-type hearts from fed mice (Fig. 3A), whereas hearts from fasted PPAR--null mice took up the same amount of glucose during the ischemic period as both fed groups. A representative immunoblot for GLUT-4 (Fig. 3B) also shows 35% lower (P < 0.05) GLUT-4 levels in hearts from fasted wild-type mice than in hearts from fed wild-type mice (Fig. 3, A and B). Hearts from fasted PPAR--null mice had the same GLUT-4 levels as those from all fed mice.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-null mouse. In all the experiments, elevations in plasma free fatty acids in wild-type mice were associated with decreased total cardiac GLUT-4, decreased cardiac glucose uptake during ischemia, and decreased recovery of contractile function during reperfusion compared with nontreated wild-type mice. However, hearts from PPAR--null mice were not affected by STZ injection, high fat feeding, and 24 h of fasting in terms of total cardiac GLUT-4 protein levels and cardiac glucose uptake during ischemia. Consequently, in the treated PPAR--null mice, myocardial recovery after ischemia was not abnormally depressed. Our results indicate that increased ischemic injury associated with high levels of circulating free fatty acids is due, at least in part, to decreased cardiac glucose uptake during ischemia caused by decreased cardiac GLUT-4 protein levels and is regulated via PPAR-.
In wild-type mice, STZ injection and high fat feeding increased plasma glucose, free fatty acids, triacylglycerol, and total cholesterol, changes consistent with the metabolic abnormalities that occur with diabetes (28). Plasma insulin was decreased in STZ-injected wild-type mice and elevated in fat-fed wild-type mice. Insulin deficiency caused a marked reduction in body weight in the wild-type, but not in the PPAR--null, mice, yet the heart weight-to-body weight ratio was not significantly elevated, as reported previously (13). As found by Trost et al. (31), the preischemic rate-pressure product was significantly lower in hearts from the STZ-treated wild-type mice than in hearts from mice subjected to the other treatments. The PPAR--null mice injected with STZ also had high plasma lipid and glucose levels, similar to those in the STZ-injected wild-type mice, but normal function. After the high-fat diet, the PPAR--null mice had dyslipidemia alone, with normal plasma glucose and insulin concentrations. Thus the PPAR--null mice were resistant to the glycemic effects of a high-fat diet but became hyperglycemic when unable to produce sufficient amounts of insulin as a result of pancreatic -cell ablation by the STZ treatment.
Fasting for 24 h increased plasma free fatty acids and decreased plasma insulin in wild-type and PPAR--null mice, with a significantly higher elevation in plasma free fatty acids in PPAR--null than in wild-type mice, as has been found by others (22). PPAR--null mice were unable to maintain body temperature or normal blood glucose levels during the fast. During a fast, the body mobilizes fat stores to the liver, where fatty acid oxidation provides ketone bodies and energy for gluconeogenesis from substrates such as glycerol, lactate, and amino acids (17). The inability of PPAR--null mice to perform effective fatty acid oxidation impaired the gluconeogenic response and resulted in low plasma glucose and low plasma 3-hydroxybutyrate (17, 29). Moreover, the inability of the rest of the body to use fatty acids impaired heat production and lowered body temperature (17, 20).
Relatively little is known about the pathology underlying diabetic cardiomyopathy, yet increasing evidence has pointed toward derangements in myocardial energy metabolism (19, 26, 27). Cardiac energy metabolism is tightly regulated to coordinate energy supply and demand (16, 28). A hallmark of the diabetic heart is decreased glucose uptake and utilization (4, 11, 19, 27, 28). Our results are consistent with these observations and show that, in STZ-injected or high-fat-fed or fasting mice, elevations in plasma free fatty acids and increased fatty acid oxidation were associated with decreased cardiac glucose uptake during ischemia.
The inhibitory effects of fatty acid oxidation on glucose metabolism in the heart were first described by Randle et al. (24) as the "glucose fatty acid cycle," which involved inhibition of pyruvate dehydrogenase by elevated levels of acetyl-CoA/CoA and NADH/NAD+ resulting from increased -oxidative flux. Our results suggest that, in addition to allosteric inhibition (24), there is also inhibition at the level of gene regulation. Other studies have indicated that cardiac-specific overexpression of PPAR- increased expression of genes involved in myocardial fatty acid utilization and simultaneously downregulated genes involved in myocardial glucose transport, glycolysis, and glucose oxidation (13, 14). In fact, these hearts showed a 50% decrease in GLUT-4 mRNA and a 70% reduction in GLUT-4 protein levels, with the PPAR- agonist Wy-14643 further enhancing this effect (14). Our results complement these studies, in that the absence of PPAR- prevented the reduction in GLUT-4 protein levels that normally accompanies diabetes and fasting (11, 19, 27, 32).
Glucose uptake and subsequent glycolysis are important to the ischemic myocardium, because it is the main source of ATP when oxidative phosphorylation is limited (8–10). The GLUT-4 transporters normally reside in vesicles near the plasma membrane and translocate to the surface during insulin stimulation or ischemic stress, acting as one of the main determinants of glycolytic flux (36). Therefore, any mechanism that could inhibit this process increases the risk of myocardial damage during ischemia. Elevated free fatty acids and intracellular lipids appear to inhibit insulin signaling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation (5). Although we did not measure GLUT-4 translocation to the sarcolemma, our results indicate lower glucose uptake during ischemia and poor recovery during reperfusion in mouse hearts with decreased total GLUT-4 protein levels. In fact, hearts from mice with a cardiac-specific ablation of GLUT-4 had profound and irreversible systolic and diastolic dysfunction with accelerated ATP depletion during low-flow ischemia (30). In obese rat hearts, decreased GLUT-4 expression was associated with decreased glucose uptake during low-flow ischemia and decreased functional recovery (27), similar to the cardiac effects of diabetes (12, 19). In the present study, STZ treatment, a high-fat diet, or a 24-h fast caused wild-type mouse hearts to recover poorly from ischemia due to decreased glucose uptake, whereas hearts from PPAR--null mice had neither increased ischemic damage nor decreased GLUT-4 protein levels or glucose uptake, suggesting that the effect was mediated by the transcription factor PPAR-. However, it is unlikely that all the observed effects occurred directly via PPAR-, because the GLUT-4 gene is not a known PPAR- target. GLUT-4 gene expression is probably repressed via PPAR--independent transcriptional regulatory pathways linked to alterations in cellular energy metabolism induced by PPAR-, as has been concluded by others (14, 15).
In summary, this work has shown that plasma free fatty acids can influence cardiac GLUT-4 levels and glucose uptake via PPAR- in three models of elevated free fatty acids: STZ injection, high fat feeding, and fasting. PPAR- activation via circulating free fatty acids resulted in decreased levels of GLUT-4 protein in the heart, thereby decreasing glucose uptake during low-flow ischemia and increasing ischemic damage.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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