© 1996 American Heart Association, Inc.
Articles |
Regulation of Very-Low-Density Lipoprotein Receptor in Hypertrophic Rat Heart
From the Department of Medicine and Clinical Science (H.M., H.J., N.M., O.N., Y.O., M.M., Y.Y., K.N.), Kyoto University Graduate School of Medicine, Kyoto, and the Tohoku University Gene Research Center (T.Y.), Sendai, Japan.
Correspondence to Hisato Jingami, MD, PhD, Department of Molecular Biology, Biomolecular Engineering Research Institute, 6-2-3 Furuedai, Suita, Osaka 565, Japan.
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Abstract |
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Abstract To elucidate the regulation of very-low-density lipoprotein (VLDL) receptor, we have studied its gene expression in the heart of spontaneously hypertensive rats–stroke prone (SHR-SP, an animal model for hypertension-induced cardiac hypertrophy) compared with Wistar-Kyoto rats. RNase protection assay showed that ventricular VLDL receptor mRNA falls to 41% of normal levels at 4 weeks, when hypertension is not yet fully developed, and drops further to 14% at 13 weeks, when cardiac hypertrophy is established. Lipoprotein lipase mRNA decreases in parallel with VLDL receptor mRNA. In cultured neonatal rat ventricular cardiomyocytes, VLDL receptor mRNA decreases in parallel with the process of cardiocyte hypertrophy during the 24 hours after treatment with 10-8 mol/L endothelin-1, falling to 40% of the initial value. These results demonstrate that there is downregulation of VLDL receptor gene expression in cardiac hypertrophy both in vivo and in vitro and suggest that the regulation of the VLDL receptor is possibly linked with the switch in energy substrate from lipid to glucose known to occur in cardiac hypertrophy.
Key Words: cardiomyocyte culture • very-low-density lipoprotein receptor • spontaneously hypertensive rats–stroke prone • cardiac hypertrophy
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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In the metabolism of fats and cholesterol, receptors for plasma lipoproteins play pivotal roles. The newly identified VLDL receptor is a specific receptor for apolipoprotein E–containing lipoproteins and is thought to play an important part in the uptake of triglyceride-rich lipoproteins chiefly in tissues that are active in fatty acid metabolism.1 2 The VLDL receptor gene is closely similar to that of the LDL receptor in both domain structure and exon-intron boundary organization, suggesting a common ancestral origin,1 2 3 4 5 but the VLDL receptor is distinct from the LDL receptor in ligand specificity and tissue distribution.1 2 3 4 The former binds specifically apolipoprotein E–containing lipoproteins, such as VLDL, intermediate-density lipoprotein, and ß-migrating VLDL, but does not bind LDL effectively.1 6 Furthermore, VLDL receptor mRNA is highly expressed in rabbit and human heart, skeletal muscle, and adipose tissue.1 2
Recently, Gåfvels et al3 demonstrated that VLDL receptor gene expression is induced during the differentiation of mouse 3T3-L1 cells into adipocytes. Bujo et al7 showed that the chicken homologue of the mammalian VLDL receptor plays an important role in reproduction.
Although the gene regulation and physiological significance of the VLDL receptor have yet to be fully elucidated,8 we have recently demonstrated that the VLDL receptor mRNA level in the cardiac ventricle is dramatically increased in response to estradiol.9 Jokinen et al10 observed the striking changes in the VLDL receptor mRNA level and protein content in the skeletal muscle of hypothyroid and hyperthyroid rats. These results suggest that the VLDL receptor plays a crucial role in the triglyceride-rich lipoprotein metabolism in those tissues. The major energy source for the heart in the basal state is free fatty acid,11 12 and the VLDL receptor gene is expressed most abundantly in the heart.1 2
It has been amply demonstrated that there is a pathological shift in the energy substrate of the heart from fatty acid to glucose during myocardial hypertrophy.13 14 15 Quantitative autoradiographic techniques such as PET and SPECT have enabled us to detect the switch in substrate preference in the hypertrophic heart by use of radiolabeled metabolic analogues of both fatty acid and glucose.16 17 18 19 20 Myocardial hypertrophy is an adaptive process responding to increased workload and is characterized by qualitative as well as quantitative changes in gene transcription, such as upregulations of "fetal-type" ß-MHC, ANP, and brain natriuretic peptide and downregulation of SR Ca2+-ATPase.21 22 23 24 25 26 27 28 29 However, the molecular mechanism for triglyceride-rich lipoprotein metabolism in the hypertrophic heart has not been studied intensively.
In the present study, to elucidate the functional role of VLDL receptor during the process of cardiac hypertrophy, we analyzed the receptor gene expression in the cardiac ventricle of SHR-SP, an animal model for hypertension-induced cardiac hypertrophy.26 27 We also determined the mRNA level of LPL, which hydrolyzes triglycerides in both VLDL and chylomicrons. Also, using a cell culture model of chemically induced cardiocyte hypertrophy,24 30 31 32 we have examined whether the alteration of the receptor mRNA level observed in vivo emerges in vitro during the process of cellular hypertrophy.
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Materials and Methods |
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Animals
Four- and 13-week-old male SHR-SP and age-matched male WKY rats were used to examine the role of the VLDL receptor during the process of cardiac hypertrophy. These rats were housed in a temperature-, humidity-, and light-controlled room with free access to water and standard rat chow (CA-1, Japan CLEA) at the Shionogi Aburahi Research Laboratories, Shiga, Japan. Two- to 4-day-old male WKY rats were used for primary cultures of neonatal rat cardiocytes.
Blood Sampling and Measurement of Serum Lipids
After
overnight (12-hour) fasting, rats were
anesthetized with pentobarbital and decapitated, and blood was
sampled for analysis of serum lipids. Total
cholesterol and triglyceride levels were
measured with an enzymatic kit (Ono Pharmacy and Wako Chemical), and
high-density lipoprotein cholesterol was determined by
the precipitation method (Dai-ichi diagnostic kit,
Dai-ichi Chemical).
Rat VLDL Receptor cDNA Cloning
We have screened the rat heart
cDNA library with the rabbit VLDL
receptor cDNA.1 One of the hybridization positive clones,
which was designated prVLDLR1, contained the entire coding region, 623
bp of the 5'-untranslated region, and 551 bp of the
3'-untranslated
region (H. Ishii and T. Yamamoto, unpublished data). DNA sequencing
revealed that the coding of this clone is identical to the coding of a
clone that Jokinen et al10 have reported.
Isolation of RNA
Soon after the animals were killed, their
tissues were quickly
dissected, snap-frozen in liquid nitrogen, and stored at
-70°C. Total RNA was isolated by the guanidine thiocyanate
method of Chirgwin et al.33 Poly(A)+ RNA was enriched with
oligo (dT) latex (Roche). The yield of poly(A)+ RNA was 
2.5% of
total RNA. In the in vitro experiments, we extracted total RNA from
cultured cardiocytes at 0, 1, 3, 6, 12, 24, and 48 hours after
ET-1 stimulation.
Northern Blot Hybridization Analysis
The procedure of
McMaster and Carmichael34 was
used. Total RNA or poly(A)+ RNA was denatured by 1 mol/L glyoxal and
50% dimethyl sulfoxide, electrophoresed on a 1.0% agarose gel,
transferred onto GeneScreen Plus nylon membrane (Du Pont–New England
Nuclear), and hybridized with cDNA probes labeled with
[
-32P]dCTP by random primer (GIBCO BRL). A 1.8-kb
EcoRI–BamHI fragment derived from prVLDLR1,
which was described above, was used as a probe. Other probes used were
as follows: a 1.5-kb Not I–EcoRV fragment
carrying human ß-actin cDNA,35 a 1.6-kb
EcoRI-EcoRI fragment carrying human LPL
cDNA,36 a 368-bp HincII–Stu I
fragment carrying rat ANP cDNA,27 and a 500-bp fragment of
rat MLC-2 cDNA.37 Prehybridization was performed at 42°C
for 2 hours in 50% deionized formamide, 6x SSC (1x SSC is 0.15
mol/L
sodium chloride and 0.015 mol/L sodium citrate), 5x Denhardt's
solution, 0.5% SDS, and 200 µg/mL denatured salmon sperm DNA.
Hybridization was carried out in the same solution plus a 2 ng/mL
32P-labeled cDNA probe with a specific activity of
1.5x109 cpm/µg. After hybridization for 16 hours at
42°C, membranes were washed serially: twice in 2x SSC at room
temperature, twice in 2x SSC with 1.0% SDS at 60°C, and twice in
0.3x SSC at room temperature. Autoradiography was
performed on x-ray films with intensifying screens (Quanta III, Du
Pont) at -70°C. The relative amount of each mRNA was determined
by densitometric scanning in the linear response range.
Solution Hybridization RNase Protection Assay
The 329-bp
Pst I–Pst I fragment carrying
rat VLDL receptor cDNA was excised and ligated with Pst
I–digested pBluescript II SK(-) (Stratagene). The subcloned
plasmid
DNA was linealized by digestion with EcoRI. The 1.58-kb
Pst I fragment encoding rat GAPDH cDNA38 was
ligated into pGEM2 vector (Promega), which was subsequently linealized
by digestion with Sau3AI. Radiolabeled RNA transcripts were
synthesized by using the linealized template DNA according to the
technical manual of Promega Corp. Briefly, 1 µg of template DNA was
transcribed by 15 U of T3 or T7 RNA polymerase with 0.5 mmol/L ATP,
GTP, and CTP, 12 µmol/L UTP, 50 µCi of
[-32P]UTP,
40 mmol/L Tris (pH 7.4), 6 mmol/L MgCl2, 2 mmol/L
spermidine, 10 mmol/L NaCl, 10 mmol/L dithiothreitol, and 20 U of
RNasin ribonuclease inhibitor. One unit of RQ1
RNase-free DNase (Promega) digestion was performed to remove the
template DNA. The cRNA probes (2x105 cpm) were hybridized
in solution (40 mmol/L PIPES [pH 6.4], 1 mmol/L EDTA, 0.4 mol/L
NaCl,
and 80% formamide) with 2 to 20 µg of total RNA at 45°C for 12
hours. RNase A (40 µg/mL, Boehringer Mannheim) was used to
digest unhybridized RNA completely, and the remaining RNA/RNA hybrid
was analyzed by 3.5% polyacrylamide gel containing 8
mol/L urea. Autoradiography and determination of
the relative amount of each RNA were performed as described in
"Northern Blot Hybridization Analysis."
Cell Culture
To analyze the receptor gene expression during
the
course of cardiocyte hypertrophy, primary cultures
of neonatal rat cardiomyocytes were prepared from the
apical halves of ventricles of 2- to 4-day-old WKY
rats.39 40 Briefly, myocardial cells were obtained
and
dispersed with agitation for 20 minutes at 37°C in balanced salt
solution (mmol/L: NaCl 116, HEPES 20, NaH2PO4
12.5, glucose 5.6, KCl 5.4, and MgSO4 0.8 [pH 7.35])
containing 0.04% collagenase II (Worthington Biochemical
Corp) and 0.06% pancreatin (GIBCO Laboratories). Cardiomyocytes
were separated from other cell types on a discontinuous Percoll
gradient and plated onto 100-mm dishes (2.0x106
cells per dish) in DMEM (Flow Laboratories) supplemented with
10% FCS. After 30 hours of incubation, cells were maintained in
serum-free DMEM for 10 hours. After this preconditioning period,
the cultures were incubated in serum-free DMEM containing 1 mg/mL
bovine serum albumin (Sigma Chemical Co) with
10-8 mol/L synthetic ET-1 (Peptide
Institute).
Statistical Analysis
Student's unpaired t test
was used to test
differences for significance. Results are expressed as mean±SD.
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Results |
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Characteristics of Plasma Lipid Profile and Cardiac Hypertrophy Between SHR-SP and WKY Rats
The Table
summarizes the results for the
SHR-SP and WKY rats used in the present study. Although the
ventricular weight and the ratio of ventricular
weight to body weight were almost equivalent in 4-week-old SHR-SP
and WKY rats, both values for SHR-SP were approximately double those of
WKY rats by the end of 13 weeks. We used the ratio of the
ventricular weight to body weight as an indicator of
ventricular hypertrophy.27
According to the ratio, marked cardiac hypertrophy
developed in SHR-SP by 13 weeks of age but was not detectable at 4
weeks. The plasma total cholesterol level was lower in
13-week-old rats than in 4-week-old rats for both SHR-SP and
WKY rats; the differences between SHR-SP and WKY rats of the same age
were statistically significant. The plasma triglyceride
level tended to be higher in 13-week-old SHR-SP than that in
age-matched WKY rats, but the difference was not statistically
significant.
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Northern Blot Analysis of VLDL Receptor and LPL mRNAs in
Ventricles of SHR-SP and WKY Rats
Poly(A)+ RNA (5 µg) from
pooled ventricular
samples of five SHR-SP and five WKY rats (4 and 13 weeks old for both)
was analyzed for VLDL receptor mRNA and LPL mRNA expression by
Northern blot analysis (Fig 1, left). Two signal
bands corresponding to VLDL receptor mRNA were detected at the size of
3.6 kb (major transcript) and 9.5 kb (minor transcript), a pattern
similar to rabbit VLDL receptor mRNA expression.1 Taking
the mRNA level in the ventricle of 4-week-old WKY rats as a
control, the VLDL receptor and LPL mRNA levels in 13-week-old WKY
rats were 1.4 times and 2.9 times higher, respectively, in Fig
1,
right. The ventricular VLDL receptor mRNA level in
4-week-old SHR-SP was <50% of that in 4-week-old WKY rats; in
13-week-old SHR-SP, this mRNA level was further reduced to 36%
compared with 13-week-old WKY rats. The ventricular LPL
mRNA level in 4-week-old SHR-SP was 65% of that in 4-week-old
WKY rats, and by 13 weeks was further diminished to 42%, paralleling
the decline of VLDL receptor mRNA. A signal corresponding to
ß-actin mRNA showed no significant difference in band density
among various groups.
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RNase Protection Assay of Ventricular Total RNA from 4-
and 13-Week-Old SHR-SP and WKY Rats
Total RNA (10 µg) from the
same pooled ventricular
samples as used in the above experiment was used to quantify the VLDL
receptor mRNA by a more sensitive procedure. A solution hybridization
RNase protection assay produced the results demonstrated in Fig
2. Ventricular VLDL receptor mRNA level in
13-week-old WKY rats increased to 140% of that in 4-week-old
WKY rats, but in 13-week-old SHR-SP, it decreased markedly to 50%
of that in 4-week-old SHR-SP. Comparing age groups, SHR-SP
ventricular VLDL receptor mRNA was 41% of WKY mRNA at 4
weeks and only 14% at 13 weeks. This assay gave results compatible
with those obtained by Northern blot analysis. A signal
intensity corresponding to GAPDH mRNA did not show significant
differences among samples.
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VLDL Receptor mRNA Level in Cultured Rat Cardiomyocytes During the
Course of Cellular Hypertrophy
To verify the presence of VLDL receptor
mRNA in
cardiocytes and to examine whether the decrement of receptor
gene expression level observed in vivo was reproducible in vitro,
cultured neonatal rat cardiomyocytes were assessed for
changes of VLDL receptor mRNA during the course of cardiocyte
hypertrophy. Cardiac myocytes and cardiac fibroblasts were
first cultured separately, and levels of VLDL receptor mRNA were
compared by RNase protection assay (Fig 3). This
revealed that VLDL receptor mRNA is higher in cardiac myocytes than in
nonmyocytes and equivalent to that in the ventricle of
2-day-old male rats. Next, we examined the change of mRNA levels in
chemically induced cardiocyte hypertrophy. Cultured
rat cardiocytes stimulated by ET-1
(10-8 mol/L) exhibited cellular
hypertrophy within 24 hours, as detected by cell surface
area measurements.39 41 A representative
result by RNase protection assay using 2 µg of total RNA per lane is
demonstrated in Fig 4, left. During 24 hours of
incubation, the VLDL receptor mRNA level declined to 40% of the
initial value in a time-dependent manner. We also analyzed
rat ANP mRNA and MLC-2 mRNA concentrations in the same sample through
Northern blot analysis to confirm the phenotypic features of
the hypertrophic cardiocytes evoked by
ET-1.28 30 31 As shown in Fig
4, left, the MLC-2 mRNA
level was gradually augmented by 12 hours after ET-1 treatment, and
there was a marked increase in cell size after 24 hours. The ANP mRNA
level began to increase 3 hours after stimulation and accumulated
rapidly. The time course of the expression of these two genes was
consistent with previous studies of cardiocyte
hypertrophy.28 30 31 The time course of
each
mRNA concentration is shown in Fig 4, right.
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Discussion |
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The purpose of the present study is to further elucidate the molecular mechanism of lipoprotein metabolism in the process of cardiac hypertrophy.
VLDL receptor mRNA is highly expressed in the heart, and the major
energy source of the heart in the basal state is free fatty acid, with
minor contributions from lactate and
glucose.10 11 12 In the
hypertrophic heart, several key enzymes in carbohydrate
metabolism are activated while fatty acid oxidation
decreases13 14 15 ; ie, there is an energy
substrate shift
from fatty acid to glucose. This switch in substrate preference is
certainly advantageous in the hypertrophic heart, which has a high
energy demand, because glucose produces more ATP per mole of oxygen
than does fatty acid.15 In the ventricle of SHR-SP, we
demonstrated that the VLDL receptor mRNA level is already decreased at
4 weeks and is further diminished at 13 weeks (Figs 1
and
2).
Furthermore, a cell culture model of cardiocyte
hypertrophy revealed that the receptor mRNA level is
likewise decreased in a time-dependent manner (Fig 4, left) and
that this decrease precedes the increase in size of cultured
cardiocytes. Downregulation of VLDL receptor mRNA expression
was also observed in cardiocytes induced to
hypertrophy by a different chemical stimulant (data not
shown). We simultaneously showed the presence of VLDL
receptor mRNA predominantly in cardiac myocytes compared with cardiac
fibroblasts (Fig 3). As shown in Fig 4, right,
we ascertained that the
gene expression pattern of ANP and MLC-2 in the present experiment
was consistent with previously reported
results.28 30 31
Although the precise mechanism and progress of cardiac hypertrophy in SHR-SP are not completely understood, our results suggest that the change in substrate selection has already taken place before cardiac hypertrophy is manifest. Our data also show that downregulation of the VLDL receptor is not an event specific to SHR-SP but is closely related to cardiocyte hypertrophy per se. Although further investigation is necessary to elucidate the kind of cell signaling that participates in the downregulation of VLDL receptor in the hypertrophic heart, decrement of VLDL receptor gene expression could be a marker in the early phase of cardiac hypertrophy.
Cardiocyte hypertrophy is characterized by
qualitative as well as quantitative changes in gene transcription. The
fetal-type ß-MHC protein has lower ATPase activity, contracts and
relaxes more slowly than "adult-type" -MHC, and therefore
improves the economy of contraction against increased
workload.21 ANP gene expression contributes to decreased
cardiac overload through natriuresis, diuresis, and
vasorelaxation24 26 27 28 and
economizes on fuel as well. SR
Ca2+-ATPase plays a fundamental role in pumping
intracellular Ca2+ during diastolic relaxation
and in modulating contraction and relaxation of the
myocardium.23 25 Because of the downregulation
of SR Ca2+-ATPase, the relengthening velocity of muscle
fibers changes slowly,24 which serves to suppress
excessive energy consumption and to increase coronary blood
flow. The switch in substrate selection and transcriptional changes in
several genes, as described above, appears to be a series of
compensatory mechanisms to meet higher demands for energy and oxygen.
The downregulation of the VLDL receptor in the hypertrophic heart
demonstrated in the present study represents one facet of
the concerted adaptations associated with the switch in energy
substrate.
It was also demonstrated that the level of LPL mRNA in the ventricle of SHR-SP decreased in parallel with the VLDL receptor mRNA. LPL plays a key role not only in energy utilization and storage but also in lipoprotein metabolism.42 LPL initially hydrolyzes triglyceride-rich lipoproteins in the capillary lumen, liberating fatty acid, which then simply diffuses into muscle and adipose tissue cells.42 The downregulation of LPL in the hypertrophic heart fits in well with the associated energy substrate shift. Tissue distribution of LPL mRNA is closely analogous to that of VLDL receptor,1 2 3 4 10 35 42 and both gene sequences are extraordinarily conserved among species.42 Furthermore, partial lipolysis of VLDL particles by LPL enhances ligand activity of apolipoprotein E.43 All these results and our data indicate that LPL and VLDL receptors could function harmoniously in triglyceride-rich lipoprotein metabolism in the heart.44
In conclusion, the present study suggests that the VLDL receptor plays an important role in the regulation of triglyceride-rich lipoprotein metabolism in the heart. Our results suggest that downregulation of the receptor in the hypertrophic heart could be a possible mechanism of adaptation to increased workload associated with a switch in energy substrate preference. Further studies of the mechanisms responsible for the local regulation of VLDL receptor in the heart may provide new insight into the pathophysiology of cardiac hypertrophy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by research grants from the Japanese Ministry of Education, Science, and Culture and the HMGCoA Reductase Foundation. We wish to thank Dr Toshio Doi for his generous gift of rat GAPDH cDNA probe, Dr Makoto Tanaka for valuable advice on RNase protection assay, Prof Toru Kita for generous support and encouragement, Dr Ian Gleadall for comments on the manuscript, and Shigeyo Sakabe for her excellent secretarial work.
Received July 6, 1995; accepted September 21, 1995.
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