Published online before print December 23, 2004, doi: 10.1161/01.RES.0000154079.20681.B9
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy
From the Center for Cardiovascular Research (H.-C.C., A.K., R.M.B., X.H., M.C., C.J.W., K.A.Y., N.S., K.M.O., D.S.O., J.E.S.) and Departments of Molecular Biology and Pharmacology (S.B., H.X., J.M.N., J.E.S.) and Radiology (M.J.W., N.M.F., T.L.S.) and Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine (X.H.), Washington University School of Medicine, St Louis, Mo.
Correspondence to Jean E. Schaffer, MD, Washington University School of Medicine, 660 S Euclid Ave, Box 8086, St Louis, MO 63110. E-mail jschaff{at}wustl.edu
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Abstract |
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Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the
-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QTc intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.
Key Words: lipids • metabolism • cardiomyopathy
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Introduction |
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Cardiomyopathy has been observed in a variety of metabolic disorders. In inherited disorders of ß-oxidation, accumulation of unmetabolized lipid in cardiac myocytes is associated with ventricular systolic dysfunction.1 In obesity, increased myocardial oxygen consumption and decreased efficiency may contribute to diastolic and systolic dysfunction.2,3 In diabetes mellitus, heart failure in the absence of valvular or congenital heart disease, alcoholism, hypertension, or significant epicardial coronary atherosclerosis is defined as diabetic cardiomyopathy and accounts for significant morbidity and mortality in people with type 1 and type 2 diabetes.4 Echocardiographic and hemodynamic studies suggest left ventricular (LV) diastolic impairment represents an early preclinical manifestation of diabetic cardiomyopathy that may progress over an extended period of time to both diastolic and systolic dysfunction.5,6
In these metabolic disorders, systemic metabolic perturbations lead to myocyte dysfunction and/or loss. Glucotoxicity,7 ATP depletion,8 and maladaptive changes in metabolic substrate utilization9 are mechanisms proposed to contribute to cardiac dysfunction. It has also been hypothesized that mismatch between tissue free fatty acid (FFA) import and utilization leads to lipid accumulation and results in lipotoxicity. In diabetes, this imbalance results from high-serum FFAs10,11 and triacylglycerols (TAGs)12 that promote excessive tissue lipid uptake, and from increased reliance on FFA as a substrate. In rodent models of poorly controlled diabetes, the observation that elevated serum FFA and TAG levels and cardiac myocyte lipid accumulation precede the development of cardiomyopathy suggest that lipid accumulation in the myocardium plays a role in the genesis of diabetic cardiomyopathy.13–15 Additionally, measures that lower cardiac lipid accumulation in these models improve cardiac function,13,16 findings that are also consistent with an important role for lipid accumulation in metabolic cardiomyopathy. Nonetheless, it is difficult to distinguish the contribution of cardiac myocyte lipid accumulation versus the contributions of global metabolic defects in the pathogenesis of any of these disorders.
To test the hypothesis that mismatch between myocardial FFA uptake and utilization leads to the accumulation of cardiotoxic lipid species results in cardiac dysfunction, a number of transgenic mouse models have been generated in which FFA uptake is driven in excess of cardiac FFA utilization independent of systemic metabolic perturbations. Cardiac overexpression of glycosylphosphatidylinositol-anchored lipoprotein lipase,17 peroxisome-proliferator–activated receptor (MHC-PPAR),18 or long-chain acyl-CoA synthetase 1 (MHC-ACS)21 each leads to lipid accumulation in the myocardium that is associated with systolic ventricular dysfunction. The findings in these models are consistent with the pathophysiological findings in end-stage metabolic cardiomyopathies.
In the present study, we have used a novel strategy to drive FFA import into the heart in excess of capacity for utilization. We have generated a transgenic (Tg) mouse model with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1), which is known to facilitate long-chain FFA import into cultured mammalian cells. Our examination of myocardial structure and function in MHC-FATP mice reveals a novel model of metabolic cardiomyopathy, characterized by diastolic ventricular dysfunction, that may serve as a model of the functional abnormalities of early diabetic cardiomyopathy.
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Materials and Methods |
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Transgenic Mice
The murine adipocyte FATP1 cDNA with an amino-terminal HA epitope tag was cloned into an
-MHC promoter construct kindly provided by J. Robbins20 and used for microinjection into FVB/N mouse embryos. PCR and Southern analysis was used to screen for founders and transgenic mice. FVB/N mice were purchased from Taconic (Germantown, NY). Animals were treated in accordance with approved Washington University Institutional Animal Care and Use Committee protocols.
Western Blot Analysis for FATP1 and Transgene Expression
Proteins were prepared from various organs of Tg and WT littermates (16- to 30-day-old) and analyzed by Western blotting as described.21 Bands were quantified by densitometry.
Serum Analysis
After a 4-hour fast, blood was obtained from 40-day-old mice from the retro-orbital plexus. Serum was separated and analyzed for TAGs, cholesterol, glucose, FFAs, and insulin levels by the CNRU Animal Model Research Core and Department of Pediatrics Developmental Biology Unit in Washington University School of Medicine, St. Louis.
1-11C-Palmitate Biodistribution and Micro-Positron Emission Tomography
Biodistribution studies were performed on 3-month-old mice after intravenous injection of 11C-palmitate. Five minutes after injection, animals were euthanized and radiolabel distribution quantified in various organs.
Myocardial fatty acid utilization (which reflects uptake, metabolism, and storage) was assessed by micro-positron emission tomography (microPET) imaging, using 11C-palmitate (300 to 400 µCi) in 3-month-old mice in the fed state. Under isoflurane inhaled anesthesia, 1-[11C]-palmitate was injected via a right jugular vein catheter. Dynamic data were acquired over 20 minutes in a Concorde MicroSystems microPET-R4 scanner in 4 pairs of mice.
Metabolism in Isolated Working Hearts
Glucose and fatty acid utilization were measured in Tg and WT hearts using 14C-glucose and 3H-palmitate in an isolated working heart preparation as previously described.22 Perfusate contained 0.4 mmol/L palmitate bound to 3% fatty acid free bovine serum albumin and 100 µU/mL insulin.
Histology
Mice were euthanized (carbon dioxide asphyxiation), and ventricular structures were isolated and fixed in formalin overnight. Paraffin-embedded sections were stained with hematoxylin and eosin (H&E) or Masson’s trichrome.
Tissue Lipid Analysis
Lipids were extracted from 20-day-old mouse ventricles using a modified Bligh and Dyer technique and analyzed by mass spectrometry as described.23 All values for lipid analysis are presented as the mean (n=5 or 6 in each group) ±SE.
Echocardiography
Longitudinal noninvasive transthoracic echocardiograms were performed as described previously.24
Hemodynamic Studies
Mice were anesthetized with thiopental sodium (60 mg/kg), intubated, and ventilated. Measures of LV systolic and diastolic function were obtained using a Millar 1.4 Fr micromanometer catheter as described.24
Electrophysiology
Ventricular myocytes from adult (2- to 3-month-old) Tg mice and WT littermates were isolated,25 and electrophysiological recordings were performed as described.26
Electrocardiography Recordings
Radiofrequency transmitters were implanted in abdominal cavities of 60-day-old FATP1 Tg mice and WT littermates under anesthesia. After recovery from surgery, telemetry was performed in the Mouse Physiology Core of the Center for Cardiovascular Research at Washington University School of Medicine on unrestrained mice as described.26
Statistics
Data are reported as the mean±SE. Differences between groups were compared by one-way ANOVA or a 2-tailed Student t test.
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Results |
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To create a model in which cardiac FFA uptake exceeds utilization, we overexpressed the murine FATP1 in cardiac myocytes using the
-myosin heavy chain gene promoter, which has been previously shown to direct cardiac-selective expression in adult mice.20 At the amino terminus of the FATP1 transgene, we included an HA epitope tag that does not interfere with protein targeting or function.27 Founders were screened by PCR and Southern blot analysis (not shown) and two independent transgenic (Tg) lines were obtained. Western blot analysis of membrane proteins from 16- to 30-day-old mouse hearts showed that each Tg line had 8-fold increased FATP1 protein expression compared with wild-type (WT) hearts (Figure 1). Transgene expression was detected in both the atria and ventricles of Tg hearts, but was not detected in lung, liver, intestine, skeletal muscle, brain, or fat tissues. Tg mice were fertile with normal litter sizes. Fasting serum glucose, FFA, and TAGs were normal [at 1 month of age, minimum of n=12 each group, Glucose (mg/dL) 213±8 WT versus 207±7 Tg; FFA (nmol/L) 0.45±0.06 WT versus 0.45±0.05 Tg; TAGs (mg/dL) 156±16 WT versus 163±13 Tg; for each measure P=ns]. For the phenotypic analysis below, findings reported for Tg mice were confirmed in both lines.
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FATP1 increases FFA transport when overexpressed in cultured mammalian cells.28 To assess the effects of transgene expression on rates of cardiac fatty acid uptake, we performed biodistribution studies using 1-11C-palmitate, an excellent tracer for FFA myocardial metabolism.29 Five minutes after injection of the radiolabeled tracer into the tail vein of anesthetized mice, organs were harvested and radioactivity quantified. Uptake of tracer into liver, kidney, and skeletal muscle was not significantly different between Tg and WT mice; however, Tg mice had a 4-fold increase in cardiac uptake of the radiolabel (Figure 2A). Thus, FATP1 overexpression in the heart leads to increased cardiac fatty acid uptake, consistent with the known effects of FATP1 overexpression in cultured cells.
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MicroPET imaging with 11C-palmitate as tracer was used to assess myocardial fatty acid utilization. Data were obtained over 20 minutes of imaging and reflects initial FFA uptake, ß-oxidation, and TAG/fatty acid intermediate formation. Imaging was completed in 4 pairs of 3-month-old Tg and WT mice in the fed state. A representative set of paired images is shown in Figure 2B demonstrating higher 11C-myocardial activity in the Tg mouse. The magnitude of increase in 11C-palmitate utilization in Tg hearts is consistent with the increase in cardiac uptake of 11C-palmitate in the biodistribution analysis.
To quantify the balance between fatty acid and carbohydrate metabolism in the heart, we analyzed hearts from Tg and WT littermates ex vivo in an isolated working heart preparation. The perfusate contained 0.4 mmol/L palmitate bound to albumin and 100 µU/mL insulin to model normal physiologic conditions. Data on oxidation of 14C-glucose and 3H-palmitate were collected over 60 minutes and rates of metabolism for each substrate were calculated per gram of dry weight of tissue. Functional measurements of the hearts (cardiac output, aortic flows, heart rate, and pressures) taken every 10 minutes indicated that the hearts maintained function throughout the experiment (not shown). Tg hearts demonstrated a 2-fold increase in palmitate oxidation and a concomitant 50% decrease in the rate of glucose metabolism (Figure 2C). Compared with previously published data from isolated working mouse hearts, glucose oxidation is higher in our 4-month old FVB wild-type mice. Differences between the absolute values obtained for glucose oxidation in our control mice and published values22 may be attributable to factors such as different ages of the mice, different background strains, overall lower heart rates in the FVB strain, and different perfusate conditions. (In the present study, insulin was included in an attempt to model the physiological substrate environment.) Nonetheless, increased delivery of fatty acid substrates to cardiac myocytes through overexpression of FATP1 in transgenic hearts is associated with a statistically significant shift in metabolism to favor utilization of long chain fatty acids.
To determine whether increased FFA uptake into the heart resulted in altered lipid homeostasis, we compared lipid content of ventricular tissue from Tg and WT mice. Flash frozen ventricular tissue from 18-day-old mice was extracted and lipids were analyzed by electrospray ionization mass spectrometry (ESI/MS) (Figure 3). FFAs were increased 2-fold in the Tg hearts compared with WT. This finding is consistent with the increased fatty acid uptake observed using 11C-palmitate and suggests that at least initially, at 18-days of age, not all of the increased fatty acid taken up is metabolized or incorporated into complex lipids. We also observed a 44% decrease in phosphatidylglycerol, suggesting effects of the transgene on overall phospholipid homeostasis. On the other hand, no differences were observed in cardiac TAG content, either at this early time point, or later at 2 and 4 months of age (by mass spectrometry and Oil Red O staining, data not shown). There were also no significant changes in cholesteryl esters, cardiolipin, phosphatidyl choline, sphingomyelin, phosphatidyl ethanolamine, or phosphatidyl serine (not shown).
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Longitudinal echocardiographic analysis was performed to assess the structure and function of MHC-FATP hearts. In Tg mice, we observed significant increases in LV mass, LV internal diameter, and left atrial size (Figure 4, Table 1). Systolic function was preserved in Tg hearts; however, the transmitral Doppler E/A ratio was significantly increased, and deceleration time was significantly decreased. Doppler tissue imaging (DTI) of the mitral annular velocity revealed preserved systolic velocity (Sa) and diminished diastolic velocity (Ea) in the Tg hearts. In addition, the ratio of early transmitral filling and diastolic mitral annular velocity (E/Ea) was increased. These abnormal filling characteristics suggest that although systolic function is preserved in these mice, LV diastolic compliance is markedly abnormal and LV filling pressure is increased. These phenotypic findings were observed beginning at 2 to 3 months of age and remained stable through the period of observation (greater than 1 year of age).
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Hemodynamic studies were performed to further assess diastolic function (Table 2). Heart rates trended lower in Tg mice, although this finding was of borderline significance. Systolic pressures (Pmax) and peak positive dP/dt were not significantly different between Tg and WT mice, consistent with normal systolic function in Tg hearts. The ratio of dP/dtmax/dP/dtmin was significantly (P<0.05) increased in Tg mice primarily attributable to a decrease in dP/dtmin. There was a trend toward increased LV filling pressure (Ped) in Tg mice that correlated with increased E/Ea observed by DTI. Tau (
), a measure of relaxation time, was increased 34% in TG mice compared with WT controls (P<0.05). Taken together, the hemodynamic and echocardiographic studies are consistent with the presence of isolated diastolic dysfunction in Tg mice.
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Pathological examination of 4-month-old Tg hearts showed remarkable differences compared with WT littermates. On gross pathological examination Tg hearts were larger, with heart weight to body weight ratios of 6.5±0.5 for Tg mice compared with 4.9±0.3 for WT mice (online Figure IA, available in the online data supplement at http://circres.ahajournals.org). These observations are consistent with the echocardiographic findings of increased LVM and LA size. Microscopically, Tg hearts demonstrated cardiomyocyte hypertrophy, overall preserved tissue architecture, and patchy mononuclear infiltrates (online Figure IB and IC). Focal interstitial fibrosis was also present in Tg hearts (online Figure ID and IE).
Despite these functional and pathological findings, we observed no progression to systolic dysfunction and no general increase in mortality in male or nonpregnant female Tg mice up to 1 year of age. However, unlike WT females, which tolerated pregnancy without difficulty, each of 6 Tg females used as breeders died during pregnancy (n=1) or during the early postpartum period (n=5). These animals were tachypneic and cyanotic before death. In contrast, nonpregnant Tg females had no increase in mortality and maintained normal systolic function. These observations suggest that the hemodynamic load and/or metabolic stress of pregnancy promoted a transition from compensated diastolic dysfunction to congestive heart failure.
During echocardiographic and hemodynamic analyses, we observed that heart rates in Tg mice trended slower than in WT littermates. It was important to confirm and quantify this difference in the absence of anesthesia, which can contribute to bradycardia even in WT mice. Thus, we implanted ambulatory ECG monitors in 3-month-old Tg and WT mice and performed ambulatory ECG monitoring. Tg mice had heart rates that were on average 22% lower than WT littermates (Figure 5). This difference was accompanied by a 22% increase in the QTc interval. Both of these differences were statistically significant. There was a trend toward increased PR in Tg mice that did not reach statistical significance. These findings suggest that the perturbations of lipid homeostasis in cardiac myocytes of MHC-FATP mice also affected conductance properties of the myocardium.
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To assess the cellular basis for these electrophysiological findings, voltage clamp studies on single isolated ventricular myocytes were undertaken. Depolarization-activated outward K+ currents, evoked during 4.5-second depolarizing voltage steps to potentials between –40 and +40 mV from a holding potential of –70 mV, were recorded in myocytes isolated from the left (LV) and right (RV) ventricles of WT and Tg mice. As illustrated in Figure 6, mean±SE peak outward K+ current densities were lower in both RV and LV myocytes isolated from Tg animals compared with RV and LV cells isolated from WT animals. Analysis of the decay phases of the outward K+ currents25 revealed that the attenuation of peak outward K+ currents in the Tg myocytes reflects the selective attenuation of IK,slow densities (Figure 6B). Ito,f and ISS densities, in contrast, were not significantly different in Tg and WT myocytes. The attenuation of IK,slow likely underlies the QT interval prolongation in this cardiomyopathic model.
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Discussion |
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The vertebrate heart relies predominantly on metabolism of long-chain FFAs that are taken up from the circulation. Proteins at the plasma membrane of cardiac myocytes, such as FATP1,28 FATP4,30,31 FATP6,32 and CD3633 may play a role in facilitating and/or regulating FFA import into this tissue. In the MHC-FATP mice, increased cardiac myocyte overexpression of FATP1 leads to increased uptake in the setting of normal plasma substrate concentrations. Whereas FATP1 overexpression increases FFA uptake into cultured cells,28 this model provides the first demonstration that FATP1 overexpression in vivo augments import of FFAs into tissues. Increased uptake of FFA in this model is associated with increased FFA metabolism that may result from increased substrate supply. However, accumulation of FFAs in these hearts suggests that the magnitude of the increase in FFA import exceeds the ability of the heart to upregulate metabolism.
In MHC-FATP mice, perturbation of lipid homeostasis results in functional abnormalities consistent with metabolic cardiomyopathy. In two independent lines, echocardiographic and hemodynamic studies suggest predominant impairment of diastolic function. Increase in E/A ratio and decrease in deceleration time observed by transmitral Doppler imaging are consistent with a restrictive filling pattern that has been observed late in the course of human diastolic dysfunction.34 Although the echocardiographic evaluation of diastolic dysfunction is difficult and has traditionally relied primarily on parameters that are load dependent, our findings by DTI and hemodynamic study confirm that there is isolated diastolic impairment in MHC-FATP mice. Differences in the degree of diastolic dysfunction by cardiac catheterization (eg, increase in Ped did not reach statistical significance) and the degree of diastolic dysfunction by echo may reflect the different loading conditions under which these analyses are performed (lightly anesthetized, semiconscious for echocardiography versus deeply anesthetized for cardiac catheterization). We hypothesize that perturbation of lipid homeostasis in MHC-FATP mice causes lipotoxicity. We did not observe cardiac myocyte apoptosis in MHC-FATP hearts (not shown). Rather than lipid-induced cell death, lipotoxicity in this model is manifest as impaired cardiac myocyte dysfunction in Tg mice that contributes significantly to altered compliance of the myocardium. Hypertrophic growth and focal fibrosis in this model may also contribute to diminished compliance.
In addition to effects on overall cardiac performance, perturbation of lipid homeostasis in MHC-FATP mice has effects on electrical properties of the heart. The QT prolongation observed with ambulatory ECG monitoring is consistent with the observed reductions in repolarizing, voltage-gated K+ currents, specifically the attenuation of Ik,slow.35,36 Recent studies have demonstrated that mouse ventricular Ik,slow has two molecular components, Kv1.5 and Kv2.1.37 Although the expression levels of the Kv1.5 and Kv2.1 proteins in cellular homogenates from MHC-FATP and WT mice are indistinguishable (not shown), the changes in lipid homeostasis in MHC-FATP ventricular myocytes may alter membrane structure or change direct interactions between lipid species and channel subunit proteins, either of which may affect channel function.38–40
Although MHC-FATP mice have normal fasting glucose, FFAs, and TAGs, the pathophysiological findings in the Tg hearts are reminiscent of abnormalities in diabetic cardiomyopathy. First, diastolic dysfunction is commonly observed early in diabetic cardiomyopathy.6 Second, QT prolongation is prevalent in individuals with type 1 and type 2 diabetes and is a predictor of cardiac mortality.41,42 Although many groups have postulated that human diabetic cardiomyopathy may result from metabolic perturbations, the relative contributions of hyperglycemia and hyperlipidemia are not known. Our findings in the MHC-FATP mouse model are consistent with the hypothesis that the hyperlipidemia associated with diabetes is central to the pathogenesis of diabetic cardiomyopathy. It is possible that both FFA accumulation as well as a maladaptive change in cardiac substrate utilization contribute to cardiomyopathy in our MHC-FATP mice and in diabetic models.
The prominence of diastolic dysfunction in the MHC-FATP mice distinguishes this model from several previously described models of lipotoxic cardiomyopathy. Several rodent models of poorly controlled diabetes show a predominance of systolic dysfunction. In the obese ZDF rat, elevated serum FFAs and TAGs are associated with cardiac lipid accumulation and depression of systolic function, as quantified by invasive hemodynamics14 and echocardiography.13 In streptozotocin-treated mice15 and in db/db43 mice, there is echocardiographic evidence for both systolic and diastolic dysfunction. Furthermore, two nondiabetic transgenic mouse models in which lipid homeostasis is perturbed demonstrate systolic impairment. Although lipid accumulation in MHC-ACS21 and MHC-PPAR18 transgenic models leads to heart failure, systolic dysfunction in these models is not preceded by diastolic dysfunction. Nor is significant diastolic dysfunction observed in MHC-ACS or MHC-PPAR lines with low-level transgene expression (unpublished studies from our laboratory and Daniel Kelly’s, 2004) is not observed in line. Differences between these models and MHC-FATP mice likely reflect differences in the specific lipid species that accumulate and/or the metabolic fate of the excess lipid in the heart. Although echocardiographic evidence of isolated alterations in LV relaxation have been reported in some rodent models of diabetes,44–46 our study is the first to provide a direct link between perturbations of lipid homeostasis and diastolic dysfunction.
The present study supports the hypothesis that altered lipid homeostasis in the heart has untoward effects on cardiac function. Our findings in MHC-FATP hearts provide the first evidence that increased FFA supply to the heart, independent of systemic metabolic perturbations (eg, diabetes), adversely affects diastolic function of the heart. This model provides a new platform for assessing mechanisms that contribute to metabolic heart disease. In future studies, MHC-FATP mice may serve as a model in which to test strategies for preventing or treating metabolic cardiomyopathy that may ultimately be translated to the care of patients with obesity, the metabolic syndrome, and diabetes.
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Acknowledgments |
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This work was supported by grants from the NIH (HL61006, T32 DK07296, P30 DK52574, P60 DK20579, P30 DK56341, P01 HL5728, 5P01 HL13851) and the American Heart Association (EIA 0040040N).
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Footnotes |
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*Both authors contributed equally to this work.
Original received February 26, 2004; resubmission received October 28, 2004; revised resubmission received December 9, 2004; accepted December 13, 2004.
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