1 Division of Cardiology, Department of Pediatrics, University of Washington, School of Medicine, Seattle 98195; 3 Children's Hospital and Regional Medical Center, Seattle, Washington 98105; and 4 University of Hamburg School of Medicine, 20246 Hamburg, Germany.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Triiodothyronine (T3) exerts direct action on
myocardial oxygen consumption (MO2),
although its immediate effects on substrate metabolism have not been
elucidated. The hypothesis, that T3 regulates substrate
selection and flux, was tested in isovolumic rat hearts under four
conditions: control, T3 (10 nM), epinephrine (Epi), and
T3 and Epi (TE). Hearts were perfused with
[1,3-13C]acetoacetic acid (AA, 0.17 mM),
L-[3-13C]lactic acid (LAC, 1.2 mM),
U-13C-labeled long-chain free fatty acids (FFA, 0.35 mM),
and unlabeled D-glucose (5.5 mM) for 30 min. Fractional
acetyl-CoA contribution to the tricarboxylic acid cycle (Fc) per
substrate was determined using 13C NMR and isotopomer
analysis. Oxidative fluxes were calculated using Fc, the respiratory
quotient, and M
O2. T3
increased (P < 0.05) FcFFA, decreased
FcLAC, and increased absolute FFA oxidation from 0.58 ± 0.03 to 0.68 ± 0.03 µmol · min
1 · g dry wt
1
(P < 0.05). Epi decreased FcFFA and
FcAA, although FFA flux increased from 0.58 ± 0.03 to
0.75 ± 0.09 µmol · min
1 · g dry
wt
1. T3 moderated the change in
FcFFA induced by Epi. In summary, T3 exerts
direct action on substrate pathways and enhances FFA selection and
oxidation, although the Epi effect dominates at a high work state.
metabolism; mitochondria; free fatty acids; nuclear magnetic resonance
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
SEVERAL HORMONES MEDIATE CHANGES in substrate supply or metabolic pathways, which control reductions in equivalent delivery to the tricarboxylic acid cycle (TCA) during variations in energy utilization and demand (7, 11). This regulatory process influences cytosolic and mitochondrial NAD redox state, as well as cytosolic phosphorylation potential (19, 35). Thus hormones participate in the integration of systems that either directly or indirectly determine the free energy of ATP hydrolysis and thus the efficiency of oxygen utilization.
Modulation of myocardial substrate pathways by hormones such as insulin, glucagon, and catecholamines has been investigated in detail (7). Although thyroid hormone is often implicated as a regulator of substrate pathways, relatively few studies involving its rapid action on cardiac metabolism have been published. This is surprising, because triiodothyronine has recently received attention as a therapeutic agent for myocardial dysfunction during several clinical conditions (17, 26, 31). Thyroid hormone, 3,3',5-triiodo-L-thyronine (T3), modulates myocardial energy metabolism, principally through nuclear-mediated regulation of specific enzyme systems (30). These include enzymes that facilitate substrate entry into the TCA, as well as those that regulate nucleoside transport into the mitochondria (2, 8, 30). T3 also elicits immediate and probably direct effects on cardiac metabolism through actions at the plasma or mitochondrial membrane (18, 20).
Immediate thyroid action on myocardial metabolism might be caused by T3-promoted changes in substrate utilization or preference. Some investigators have shown that T3 binds directly to the mitochondrial membrane and alters function of specific enzyme systems (38, 39). In particular, Sterling (38) and Sterling and Brenner (39) demonstrated immediate action by T3 at the adenine nucleotide translocator in liver mitochondria (38, 39). Others have shown rapid T3 action on enzymes that regulate long-chain fatty acid synthesis in liver (25, 37). These findings imply that T3 exerts direct and immediate actions at the mitochondrial membrane that could alter and possibly enhance fatty acid metabolism. Some thyroid action has been attributed to changes in myocardial sensitivity to catecholamines, such as epinephrine (1, 4, 40). However, other studies indicate that catecholamines inhibit acute stimulatory effects of T3 on cytosolic Ca2+ entry, which may play a role in activation of some substrate pathways (16).
Accordingly, this study's primary objective was to test the hypothesis that T3 alters myocardial substrate selection rapidly and through other than nuclear-mediated mechanisms. A secondary objective was to determine whether metabolic synergism exists between thyroid hormone and epinephrine. Additionally, thyroid hormone action could change at higher rates of oxygen consumption induced by catecholamine stimulation. These experiments, performed in isolated rat hearts, used 13C magnetic resonance spectroscopy with isotopomer analysis (15, 22, 23) to determine relative substrate contribution to the TCA cycle.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Materials. Standard reagents were obtained from Sigma Chemical (St. Louis, MO). [1,3-13C]acetoacetic acid (99.0 atom percent), L-[3-13C]lactic acid (sodium salt), and D-[U-13C6]glucose were obtained from Isotec (Miamisburg, OH). Long-chain fatty acid preparations uniformly enriched with 13C to 99% were obtained from Martek (Columbia, MD). The fatty acid preparation consisted of the sodium salts of the following acids: palmitic (23.2%), palmitoleic (4.4%), hexadecadienoic (10.7%), hexadecatrienoic (7.6%), oleic (12.0%), linoleic (26.2%), and linolenic (10.0%). Fatty acid-free bovine serum albumin (fraction V), 3,3',5'-triiodo-L-thyronine (free acid), and deuterium oxide (2H2O) were obtained from Sigma Chemical. Animal procedures were in accordance with guidelines of the University of Washington Animal Care Committee and the National Institutes of Health.
Acetoacetate-[1, 3-13C]ethyl ester (22.2 µl) was hydrolyzed in 40 ml of deionized water to acetoacetate at pH 12.0 (1 M NaOH) (13). After 2.5 h, the pH was adjusted to ~7.2 with 1 M HCl before addition to 1 liter of physiological salt solution (PSS) for perfusion.Heart perfusion.
Male Sprague-Dawley rats weighing 350-450 g were anesthetized with
pentobarbital sodium (45 mg/kg ip) and heparin (700 U/kg ip). The heart
was rapidly excised and immersed momentarily in ice-cold PSS (pH 7.4)
containing (in mmol) 118.0 NaCl, 25.0 NaHCO3, 4.7 KCl, 1.23 MgSO4, 1.2 NaH2PO4, 5.5 D-glucose, and 1.2 CaCl2. The aorta was
cannulated in the standard Langendorff mode. The heart was perfused
with PSS, which had been equilibrated with 95% O2-5%
CO2 at 37°C and passed twice through filters with
3.0-µm pore size. Perfusion pressure was maintained at 70 mmHg. An
incision was made in the left atrium, and a fluid-filled latex balloon was passed through the mitral orifice and placed in the left ventricle. The balloon was connected to a pressure transducer for continuous measurement of left ventricular pressure (LVP) and its first derivative with respect to time (LV dP/dt). The caudal vena cava, the
left and right cranial venae cavae, and the azygous vein were ligated. The pulmonary artery was incised and cannulated to enable collection of
coronary flow, which was measured with a flowmeter (T 106, Transonic
Systems, Ithaca, NY). Myocardial O2 consumption
(MO2) was calculated from the
differences in O2 content of perfusion in the supply line
and coronary effluent from the pulmonary artery, as described
previously (28).
Perfusate protocol. Spontaneously beating hearts were used throughout the experiment. After heart isolation and preparation, a left ventricular balloon volume was defined that would provide an LVDP between 100 and 140 mmHg. This volume was maintained throughout the protocol. Hearts were excluded from statistical analyses if this volume produced EDPs >8 mmHg. All hearts were initially stabilized via perfusion for 30 min with the indicated standard PSS buffer. The perfusate was switched to PSS containing 13C-labeled substrates: 0.17 mM acetoacetate-[1,3-13C2]ethyl ester, 1.2 mM L-[3-13C]lactic acid, and 0.35 mM of U-13C-labeled long-chain free fatty acids (FFA) bound to 0.75% (wt/vol) delipidated bovine serum albumin reconstituted with deionized water. The substrate concentration of this mixture conforms to physiological concentrations in rat artery, as reported by Remesy and Demigne (32). However, acetoacetate supplied the entire ketone body composition for labeling purposes. The entire perfusion system was jacketed and maintained at 37 ± 1°C.
The labeling patterns of the 13C-enriched substrates were selected to quantify unambiguously the contribution of exogenous substrates to acetyl-CoA. The hearts were divided into four groups. The control group (C) was perfused for 30 min with the perfusate containing the 13C-labeled substrates. The T3 group was supplied with triiodothyronine diluted in 1 N NaOH (34) at the onset of the 30-min period of perfusion at a perfusate concentration of 10 nM. The epinephrine (Epi) group received epinephrine in the 13C-labeled perfusate at a final concentration of 1 µM, also at the onset of the 30-min perfusion period. The fourth group, TE, was subject to treatment with both T3 and Epi in the perfusate at the same concentrations as with the individual reagents. Functional and metabolic parameters were recorded every 5-10 min. After 60 min of total perfusion, nonventricular tissue was removed, and hearts were freeze-clamped with copper tongs that had been chilled in liquid nitrogen.Extraction.
One gram of the frozen tissue was ground into fine powder by use of a
mortar and pestle under liquid nitrogen and transferred into four
Eppendorf tubes, each containing 1 ml of 3.5% cold perchloric acid
(4°C). The acid extraction was centrifuged for 25 min at 20,800 g to remove insoluble tissue. The supernatant was
neutralized with 5 M KOH to pH 2, with 1 M KOH to pH 5, and finally
with 0.1 M KOH to pH 7.4. The neutralized samples were spun for 15 min at 20,800 g to remove insoluble KClO4 salts. The
final supernatant was lyophilized at 50°C overnight and stored at
80°C for later NMR analysis.
13C NMR and isotopomer analysis. Lyophilized heart extracts were dissolved in 0.5 ml 2H2O (99.8%) for NMR spectral acquisition. 13C NMR spectra of the samples were acquired at 125.7 MHz on a Bruker AM 500 spectrometer with a 45° pulse and a 3-s recycle delay by use of 16-K data points to digitize 13 kHz. Protons were decoupled with a Waltz-16 decoupling scheme. Before Fourier transformation, the free-induction decays were baseline corrected and zero-filled. Generally, spectra with adequate signal-to-noise ratio were obtained in 4-5 h.
All of the labeled carbon resonances (C1 to C5) of glutamate were integrated using the Lorentzian peak-fitting subroutine in the acquisition program (Tecmag MacFID 1D 5.2). The raw integral values were entered into a spreadsheet to calculate ratios of components in each carbon's multiplet pattern. These ratios were used as starting parameters for the TCA analysis-fitting algorithm. The TCA analysis software, tcaSIM and tcaCALC, were provided by Dr. C. R. Malloy and Dr. F. M. Jeffrey through the website www2.swmed.edu/rogersmr2/.Statistical analyses. Reported values are means ± SE. The Statview 4.5 (FPV) program (1995, Abacus Concepts, Berkeley, CA) was used for statistical analysis. Data were evaluated with repeated-measures analysis of variance (ANOVA) within groups and single-factor ANOVA across groups. When significant F values were obtained, individual group means were tested for differences using the unpaired t-test. The criterion for significance was P < 0.05 for all comparisons.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cardiac function parameters.
No significant changes in heart rate occurred with either Epi or
T3 infusion. LVDP and maximum DP/dt increased
with Epi alone and in combination with T3 but did not
change with T3 infusion alone. Figures
1 and 2
illustrate these parameters through the protocols and demonstrate
achievement of steady-state levels of function.
|
|
MO2.
Elevation in M
O2 occurred with Epi and
with TE treatments. Statistical comparisons with baseline and control
groups are shown in Fig. 3.
T3 alone did not elicit a change in
M
O2. After the initial
M
O2 increase (1 min) in the two groups
receiving Epi, a steady rate was achieved.
M
O2 did not change significantly when
compared with the 1-min value. Changes in
M
O2 resulted from combined alterations
in both coronary flow and oxygen extraction. However, these indexes did
not change significantly when analyzed individually. Coronary flow in
the Epi groups exhibited the greatest range, extending from 42.8 ± 5.1 at baseline to 52.7 ± 2.5 ml · min
1 · g dry wt
1 at
peak. Similar baseline values occurred in the C and T3
groups, with minimal detectable change through the protocol.
|
Isotopomer analysis.
Several previous publications have described 13C isotopomer
modeling and analyses (13). An example of raw spectra and
synthetic corresponding spectra generated by the Lorentzian fit routine is demonstrated in Fig. 4. The control
heart spectrum at C4 (Fig. 4) yielded a quartet from
coupling between labels at C4. At the two adjacent sites,
C3 and C5, a doublet, D45, arises
from coupling between labels at C4 and C5. A
doublet, D34, arises from similar coupling between labels
at C4 and C3, and a singlet results from label
at C4, but with no adjacent labeling.
|
Substrate selection.
Acetyl-CoA enters the TCA cycle either through the acyl-CoA synthase or
pyruvate dehydrogenase pathways. Fractional acetyl-CoA contributions of
individual substrates were determined in these experiments from
13C isotopomer analyses. Representative spectra from each
experimental condition are shown in Fig.
5. Differences in specific resonance patterns among the various conditions can be noted. For instance, the
singlet in the C4 region predominates relative to other spectra from
the epinephrine-infused heart. Anaplerosis contribution to the TCA was
also calculated. However, the anaplerotic contribution never exceeded
4% in these protocols.
|
|
Substrate flux.
The 13C isotopomer analyses do not directly provide
absolute measures of substrate flux. However, Jeffrey et al.
(14) derived equations for estimating citric acid cycle
and substrate flux when TCA fractional enrichment and total
MO2 rates are known (see Ref.
14 for details). In general, this method utilizes an
assumed respiratory quotient (R) value
(M
O2/TCAflux) for each
substrate, where R is 2 for AA, 3 for LAC, and 2.8 for FFA. The
composition of the endogenous (end) substrate contribution was not
determined but was greatest during Epi stimulation. Because previous work indicates that this contribution is provided through glycogen and endogenous triglycerides, an R value of 2.9 is assumed. Thus M
O2/TCAflux = FcFFARFFA + FcLACRLAC + FcAARAA + FcendRend + yRa, where Fc is
the fractional contribution to TCA from each substrate, and
yRa represents the anaplerotic component. Because anaplerosis contributes <4% to total oxygen consumption even at high
workloads (14), this component is considered negligible for these experimental calculations. Flux through the TCA, which is
synonymous with oxidation rate for each substrate, can be calculated by
normalizing individual TCAflux values to the number of
acetyl-CoA esters yielded per molecule of that substrate, e.g., LAC 1, AA 2, and FFA 8.5. Results of these calculations are summarized in Table 2. Epi substantially increases TCA
flux, defined as the overall acetyl-CoA oxidation rate. T3
increases FFA flux through the TCA and diminishes lactate flux.
Although the FFA Fc is reduced by Epi, the absolute oxidation rate is
increased substantially. Acetoacetate flux is reduced by Epi, whereas
lactate oxidation is increased. Statistical comparisons between the Epi
and the TE groups reveal no significant differences between these
groups with regard to Fc values or calculated flux rates. Thus these comparisons between groups indicate that responses to Epi or high work
state are not directly modified by T3. However, although Epi lowers FcFFA relative to the C group, this effect is
ameliorated by addition of T3. Furthermore, the TE group
demonstrates a significantly higher FcLAC than the C group,
which is not demonstrated in the Epi group.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Evidence for thyroid promotion of myocardial fatty acid utilization represents the principal and novel finding in this study. The 13C isotopomer analyses, combined with oxygen consumption measurement, provide the Fc to the TCA cycle for multiple substrates, as well as absolute substrate flux calculations. Using this format, we detected T3 alterations in FFA acetyl-CoA Fc and calculated absolute FFA flux rate, which occurred independently of changes in oxygen consumption or cardiac functional parameters. Thus these data indicate that changes in substrate utilization result from hormonal action and not solely through elevations in cardiac work state.
Previously, Liu et al. (20) reported that T3 at a similar dose caused no significant change in palmitate oxidation in the isolated working heart. Their results seem to conflict with our findings, indicating that T3 promotes FFA selection and absolute oxidation rate. However, those investigators examined substrate oxidation under conditions that are substantially different from those applied in our study. The principal objective of those experiments was to determine whether T3 could improve mechanical function and cardiac function by modulation of glucose metabolism. Accordingly, the investigators proffered substrates at concentrations that would maximize palmitate oxidation rates during control and reperfusion conditions (36). Specifically, those investigators used perfusate with a relatively high palmitate concentration (1.2 mM) and containing no lactate or ketone bodies. This substrate provision differs substantially from the physiological composition used in the current study and from that used in detailed experiments with rats (32). The physiological perfusate substrate concentrations in our studies were appropriate for addressing the principal hypothesis that thyroid hormone directly promotes fatty acid oxidation and/or selection. The elevation of palmitate oxidation, possibly to near-maximal flux rates, limited the capability of detecting further increases in FFA oxidation during Liu's experiments. Thus apparent discrepancies between these studies can be explained by differences in substrate provision.
Direct thyroid hormone action presumably occurs along two principal
pathways that regulate substrate selection, those leading to the
pyruvate dehydrogenase complex and those leading to acyl-CoA synthase
(10). In the current experiments, T3 increased
FFA flux while coordinately decreasing oxidation of lactate, which represented the principal substrate source for the acetyl-CoA contribution through pyruvate dehydrogenase. This pattern supports the
postulated reciprocal mode of regulation of these pathways (33). Activation of enzymes that regulate myocardial fatty
acid utilization and/or transport provides a plausible explanation for
the T3-induced elevation in FFA acetyl-CoA Fc and absolute oxidation rate. For example, carnitine palmitoyl transferase I catalyzes the initial reaction of mitochondrial import of long-chain fatty acids. This tightly regulated transfer presumably participates in
the control of fatty acid oxidative flux rate. T3 directly diminishes utilization of exogenous [14C]palmitate for
synthesis of longer chain fatty acids in isolated rat hepatocytes
(25). This effect can be reversed by blocking fatty acid
oxidation through octanoylcarnitine, a direct carnitine palmitoyl-transferase I inhibitor, although evaluation of this phenomenon has not been reported in heart (25). Goodwin
and colleagues (9, 10) showed that -oxidation rates in
rat heart correlate inversely with malonyl-CoA levels. Thus acetyl-CoA
carboxylase, the enzyme responsible for synthesis of malonyl-CoA,
provides another candidate site for direct T3 regulation of
long-chain FFA oxidation. Further studies will be required to elucidate
the mechanisms involving activation of the FFA pathways by
T3 in heart.
A secondary objective of this study was to determine whether thyroid
hormone effects on substrate preference dominated during abrupt
increases in cardiac workload caused by Epi. Although several investigators have used Epi stimulation as a mode to examine substrate oxidation patterns during acute elevations in work state (3, 6,
9, 10), rapid thyroid hormone action under comparable conditions
has not been well investigated. Thyroid hormone promotes increases in
cardiac -adrenoreceptor density and sensitivity (12,
29). Although these actions are nuclear mediated, they provide
the general impression that thyroid and epinephrine work synergistically. This contention stems in part from studies suggesting that thyroid hormone enhances the cardiac inotropic response to epinephrine (1, 4, 40).
Accordingly, the effects of Epi in this study should be
considered in context to understand possible metabolic interactions between these two hormones. First, one must evaluate the consequences of supplying Epi alone (without T3) in the current model.
Considerable inconsistencies exist in the scientific literature with
respect to Epi influence on substrate metabolism in isolated perfused rat hearts. Early studies by Crass et al. (5) and Neely et al. (27) indicate that palmitate oxidation increases in
response to elevation in work state and/or Epi. More recently,
Collins-Nakai et al. (3) found that Epi increased ATP
production through selective increases in glucose oxidation and
glycolysis. Goodwin et al. (10) found that Epi immediately
stimulated glycogen contribution to oxidation, induced glucose
oxidation later, and caused a trend toward increased oleate oxidation
(although it was not statistically significant). Virtually all these
studies employed different protocols using a wide variety of substrate
mixtures, perfusion conditions, and methodology. Whereas Collins-Nakai
et al. perfused hearts with palmitate and glucose, but no lactate or
ketone bodies, Goodwin et al. used a complex protocol involving
glycogen depletion by substrate deprivation followed by repletion of
glycogen during perfusion with multiple substrates including lactate,
glucose, first -hydroxybutyrate, and then oleate. Thus those
attempting to make comparisons among these studies, as with the current
data, must consider the specific conditions of each experiment.
Epi in these experiments elevated the acetyl-CoA Fc through lactate and unlabeled sources. These changes in relative Fc occurred in conjunction with absolute flux increases for FFA and lactate, as well as decreases in acetoacetate Fc and absolute flux. The composition of unlabeled substrate sources cannot be strictly defined in this analysis but should include exogenous substrate, i.e., glucose, and endogenous substrates such as triglycerides and glycogen. Under baseline conditions, both with and without T3, the unlabeled substrates contribute no more than 10% of the acetyl-CoA entering the TCA. This value corresponds well to data from other studies employing 13C isotopomer techniques (13, 21), supporting the tenet that glucose contributes minimally without Epi stimulation, even if this substrate represents the entire unlabeled source. Further evidence that glucose is not a major contributor in the unstimulated state is provided by several recent studies employing 14CO2 production from labeled substrates and indicating that glucose contributes 3-20% TCA acetyl-CoA, depending on perfusate substrate composition as well as the presence or absence of insulin (3, 9, 20). The increase in Fc from unlabeled sources to 18% during Epi stimulation in our experiments could be secondary to increased unlabeled glucose oxidation. This hypothesis was considered and tested by providing a separate group of hearts with D-[U-13C6]glucose in the place of U-13C-labeled long-chain FFAs. The minimal glucose contribution (<3%) during Epi stimulation is dramatically demonstrated in the spectra illustrated in Fig. 6. Thus these experiments, employing both labeled and unlabeled glucose schemes, indicate that endogenous stores, and not glucose, are responsible for the increase in unlabeled Fc during Epi infusion. These data are consistent with experimental results reported by Goodwin et al. (9, 10), who demonstrated a burst of glycogen breakdown and oxidation, as well as elevated triglyceride turnover, early during Epi infusion. Those investigators detected subsequent increases in glucose oxidation in their working heart model, which might be delayed (5, 27) and therefore go undetected in these Langendorff heart experiments. One might question the validity of the steady-state assumptions in the current experiments, and whether errors in isotopomer analyses contributed to results indicating a minimal oxidative contribution from glucose. However, as previously noted, data were also subjected to non-steady-state analyses (24). Rigorous statistical comparisons of the data analyzed using these different models (steady state vs. nonsteady state) validated the assumptions and indicated that metabolic steady state had indeed been achieved for all protocols in these experiments.
Generally, the direct comparison data (Epi vs. TE) indicate that T3 does not substantially alter substrate selection or flux during high work state elicited by Epi. Thus no obvious synergism or cooperation existed between these two hormones with regard to substrate metabolism. The Epi influence dominated, which was manifested by the increase in calculated TCA flux and lactate oxidation rate. T3 appears to slightly modify Fc values for FFA, lactate, and unlabeled substrates when statistical comparisons of control vs. Epi are considered. The direction for FcFFA modification could be expected when one considers shifts toward FFA selection by T3 at the lower work states. The FcLAC, which demonstrated no change with Epi (vs. control), also showed a significant increase when T3 was included (C vs. TE). This finding was surprising when we consider the reduction in FcLAC by T3 at low work state. However, these data could be explained by a T3 enhancement of exogenous over endogenous substrate selection at high work state. As stated previously, because the composition of the unlabeled source is not strictly defined in these experiments, flux rates for this portion cannot be calculated. Alternative models, which employ endogenous source labeling, would be required to further evaluate T3 effects on this substrate pool at high work states.
In summary, these studies demonstrate that thyroid hormone directly and rapidly shifts myocardial substrate preference. The time frame of these experiments indicates that these responses are not nuclear mediated. Although T3 might enhance the contractile response to Epi in some models, no synergism exists with regard to FFA contribution to the TCA. These studies have particular significance because of the recently established clinical importance of T3 supplementation after cardiopulmonary bypass (26), which causes drops in circulating thyroid hormone levels. T3 supplementation improves postoperative cardiac function, although the mechanisms and their relationship to myocardial metabolism have not been established.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was funded by National Heart, Lung, and Blood Institute Grant R01-HL-60666 (M. A. Portman).
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: M. A. Portman, Cardiology CH11, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105 (E-mail: Mportm{at}chmc.org).
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.
Received 10 January 2001; accepted in final form 20 June 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Anton, AH,
and
Gravenstein JS.
Studies on thyroid-catecholamine interactions in the isolated rabbit heart.
Eur J Pharmacol
10:
311-318,
1970[ISI][Medline].
2.
Chu, R,
Madison LD,
Lin Y,
Kopp P,
Rao MS,
Jameson JL,
and
Reddy JK.
Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways.
Proc Natl Acad Sci USA
92:
11593-11597,
1995[Abstract].
3.
Collins-Nakai, RL,
Noseworthy D,
and
Lopaschuk GD.
Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism.
Am J Physiol Heart Circ Physiol
267:
H1862-H1871,
1994
4.
Coville, PF,
and
Telford JM.
Influence of thyroid hormones on the sensitivity of cardiac and smooth muscle to biogenic amines and other drugs.
Br J Pharmacol
39:
49-68,
1970[ISI][Medline].
5.
Crass, MF, III,
McCaskill ES,
and
Shipp JC.
Effect of pressure development on glucose and palmitate metabolism in perfused heart.
Am J Physiol
216:
1569-1576,
1969[ISI][Medline].
6.
Crass, MF, III,
Shipp JC,
and
Pieper GM.
Effects of catecholamines on myocardial endogenous substrates and contractility.
Am J Physiol
228:
618-627,
1975[ISI][Medline].
7.
Depre, C,
Vanoverschelde JL,
and
Taegtmeyer H.
Glucose for the heart.
Circulation
99:
578-588,
1999
8.
Djouadi, F,
Riveau B,
Merlet-Benichou C,
and
Bastin J.
Tissue-specific regulation of medium-chain acyl-CoA dehydrogenase gene by thyroid hormones in the developing rat.
Biochem J
324:
289-294,
1997[ISI][Medline].
9.
Goodwin, GW,
Ahmad F,
Doenst T,
and
Taegtmeyer H.
Energy provision from glycogen, glucose, and fatty acids on adrenergic stimulation of isolated working rat hearts.
Am J Physiol Heart Circ Physiol
274:
H1239-H1247,
1998
10.
Goodwin, GW,
Taylor CS,
and
Taegtmeyer H.
Regulation of energy metabolism of the heart during acute increase in heart work.
J Biol Chem
273:
29530-29539,
1998
11.
Hoek, JB.
Hormonal regulation of cellular energy metabolism.
In: Molecular Mechanisms in Bioenergetics, edited by Ernster L.. Amsterdam: Elsevier, 1992, p. 421-461.
12.
Hoit, BD,
Khoury SF,
Shao Y,
Gabel M,
Liggett SB,
and
Walsh RA.
Effects of thyroid hormone on cardiac beta-adrenergic responsiveness in conscious baboons.
Circulation
96:
592-598,
1997
13.
Jeffrey, FM,
Diczku V,
Sherry AD,
and
Malloy CR.
Substrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentration.
Basic Res Cardiol
90:
388-396,
1995[ISI][Medline].
14.
Jeffrey, FM,
Storey CJ,
Sherry AD,
and
Malloy CR.
13C isotopomer model for estimation of anaplerotic substrate oxidation via acetyl-CoA.
Am J Physiol Endocrinol Metab
271:
E788-E799,
1996
15.
Jeffrey, FMH,
Rajagopal A,
Malloy CR,
and
Sherry AD.
13C-NMR: a simple yet comprehensive method for analysis of intermediary metabolism.
Trends Biochem Sci
16:
5-10,
1991[ISI][Medline].
16.
Kaasik, A,
Paju K,
Vetter R,
and
Seppet EK.
Thyroid hormones increase the contractility but suppress the effects of beta-adrenergic agonist by decreasing phospholamban expression in rat atria.
Cardiovasc Res
35:
106-112,
1997[ISI][Medline].
17.
Klein, I,
and
Ojamaa K.
Thyroid hormone treatment of congestive heart failure.
Am J Cardiol
81:
490-491,
1998[ISI][Medline].
18.
Klemperer, JD,
Zelano J,
Helm RE,
Berman K,
Ojamaa K,
Klein I,
Isom OW,
and
Krieger K.
Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia.
J Thorac Cardiovasc Surg
109:
457-465,
1995
19.
Laughlin, MR,
and
Heineman FW.
The relationship between phosphorylation potential and redox state in the isolated working rabbit heart.
J Mol Cell Cardiol
26:
1525-1536,
1994[ISI][Medline].
20.
Liu, Q,
Clanachan AS,
and
Lopaschuk GD.
Acute effects of triiodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat hearts.
Am J Physiol Endocrinol Metab
275:
E392-E399,
1998
21.
Malloy, CR,
Jones JG,
Jeffrey FM,
Jessen ME,
and
Sherry AD.
Contribution of various substrates to total citric acid cycle flux and anaplerosis as determined by 13C isotopomer analysis and O2 consumption in the heart.
Magma
4:
35-46,
1996[Medline].
22.
Malloy, CR,
Sherry AD,
and
Jeffrey FM.
Carbon flux through citric acid cycle pathways in perfused heart by 13C NMR spectroscopy.
FEBS Lett
212:
58-62,
1987[ISI][Medline].
23.
Malloy, CR,
Sherry AD,
and
Jeffrey FM.
Analysis of tricarboxylic acid cycle of the heart using 13C isotope isomers.
Am J Physiol Heart Circ Physiol
259:
H987-H995,
1990
24.
Malloy, CR,
Thompson JR,
Jeffrey FM,
and
Sherry AD.
Contribution of exogenous substrates to acetyl coenzyme A: measurement by 13C NMR under non-steady-state conditions.
Biochemistry
29:
6756-6761,
1990[ISI][Medline].
25.
Muci, MR,
and
Gnoni GV.
Short-term effects of triiodothyronine on exogenous and de novo synthesized fatty acids in rat hepatocytes.
Biochem Int
25:
807-813,
1991[ISI][Medline].
26.
Mullis-Jansson, SL,
Argenziano M,
Corwin S,
Homma S,
Weinberg AD,
Williams M,
Rose EA,
and
Smith CR.
A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery.
J Thorac Cardiovasc Surg
117:
1128-1134,
1999
27.
Neely, JR,
Bowman RH,
and
Morgan HE.
Effects of ventricular pressure development and palmitate on glucose transport.
Am J Physiol
216:
804-811,
1969[ISI][Medline].
28.
Ning, XH,
Xu CS,
Song Y,
Xiao Y,
Hu YJ,
Lupinetti F,
and
Portman M.
Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia.
Am J Physiol Heart Circ Physiol
274:
H786-H793,
1998
29.
Novotny, J,
Bourova L,
Malkova O,
Svoboda P,
and
Kolar F.
G proteins, beta-adrenoreceptors and beta-adrenergic responsiveness in immature and adult rat ventricular myocardium: influence of neonatal hypo- and hyperthyroidism.
J Mol Cell Cardiol
31:
761-772,
1999[ISI][Medline].
30.
Portman, M,
Xiao Y,
Tucker RL,
Parish SM,
and
Ning XH.
Thyroid hormone coordinates respiratory control maturation and adenine nucleotide translocator expression in heart in vivo.
Circulation
102:
1323-1329,
2000
31.
Portman, MA,
Fearneyhough C,
Ning X,
Duncan B,
Rosenthal G,
and
Lupinetti F.
Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart surgery.
J Thorac Cardiovasc Surg
120:
604-608,
2000
32.
Remesy, C,
and
Demigne C.
Changes in availability of glucogenic and ketogenic substrates and liver metabolism in fed or starved rats.
Ann Nutr Metab
27:
57-70,
1983[ISI][Medline].
33.
Saddik, M,
Gamble J,
Witters LA,
and
Lopaschuk GD.
Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart.
J Biol Chem
268:
25836-25845,
1993
34.
Samuels, HH,
Tsai JS,
and
Cintron R.
Thyroid hormone action: a cell-culture system responsive to physiological concentrations of thyroid hormones.
Science
181:
1253-1256,
1973[ISI][Medline].
35.
Scholz, TD,
Laughlin MR,
Balaban RS,
Kupriyanov VV,
and
Heineman FW.
Effect of substrate on mitochondrial NADH, cytosolic redox state, and phosphorylated compounds in isolated hearts.
Am J Physiol Heart Circ Physiol
268:
H82-H91,
1995
36.
Schonekess, BO.
Competition between lactate and fatty acids as sources of ATP in the isolated working rat heart.
J Mol Cell Cardiol
29:
2725-2733,
1997[ISI][Medline].
37.
Schonfeld, P,
Wieckowski MR,
and
Wojtczak L.
Thyroid hormone-induced expression of the ADP/ATP carrier and its effect on fatty acid-induced uncoupling of oxidative phosphorylation.
FEBS Lett
416:
19-22,
1997[ISI][Medline].
38.
Sterling, K.
Thyroid hormone action: identification of the mitochondrial thyroid hormone receptor as adenine nucleotide translocase.
Thyroid
1:
167-171,
1991[Medline].
39.
Sterling, K,
and
Brenner MA.
Thyroid homone action: effect of triiodothyronine on mitchondrial adenine nucleotide translocase in vivo and in vitro.
Metabolism
44:
193-199,
1995[ISI][Medline].
40.
Tielens, ET,
Forder JR,
Chatham JC,
Marrelli SP,
and
Ladenson PW.
Acute L-triiodothyronine administration potentiates inotropic responses to beta-adrenergic stimulation in the isolated perfused rat heart.
Cardiovasc Res
32:
306-310,
1996[ISI][Medline].