(Circulation. 2001;103:442.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17
Evaluation of Cardiac Ryanodine Ryr2 Receptor as a Candidate
From the Section on Clinical Pharmacology (L.Z., A.S., D.J.R.N., L.L., M.R.W.) and Cardiac Medicine (A.J.W.), National Heart and Lung Institute, Imperial College School of Science, Technology, and Medicine, London, UK; the Department of Genetics and Biometry (C.S.H.), Roslin Institute, Edinburgh, UK; and Université Libre de Bruxelles (J.S., C.S.), Institut de Biologie et de Médecine Moléculaires, Rue Profs Jeener et Brachet, Gosselies, Belgium.
Correspondence to Prof M.R. Wilkins, Section on Clinical Pharmacology, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. E-mail m.wilkins{at}ic.ac.uk
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Abstract |
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Background—Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response.
Methods and Results—Male F2 offspring from an F344xWKY intercross were exposed to hypoxia (10% O2) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F2 population and was independent of pulmonary artery pressure. The peak was centered over marker D17Rat41, close to Chrm3, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 within our QTL. [3H]Ryanodine binding to cardiac membranes from the parental strains showed a 21% reduction in Bmax in the WKY compared with the F344 strain, with no difference in Kd.
Conclusions—These data provide the first demonstration of a QTL linked to the RV response to hypoxia-induced pulmonary hypertension. The Ryr2 receptor gene lies within this QTL and merits further investigation as a candidate for this differential RV response.
Key Words: genetics • hypertrophy • hypoxia
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Introduction |
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The normal adult pulmonary circulation is a low-pressure low-resistance system with little or no resting vascular tone. The thin walls of pulmonary vessels and the relatively thin-walled right ventricle (RV) (compared with the left ventricle [LV]) reflect this low hemodynamic stress. Pulmonary artery pressure is increased by chronic hypoxia (eg, in patients with obstructive airway disease or people living at high altitude), and this leads to RV hypertrophy and premature death.1 2
The initial rise in pulmonary artery pressure during exposure to hypoxia is due to vasoconstriction. Chronic hypoxia leads to structural remodeling of pulmonary vessels and RV hypertrophy, features that are common to a number of species, including the rat.3 A number of pathological abnormalities have been described in the pressure-overloaded hypertrophied RV, which can impair myocardial hypertrophy, including polymerization of microtubules in cardiac myocytes4 and stimulation of interstitial collagen deposition.5 However, the biochemical processes involved in the hypertrophic myocardial response to pressure overload remain unclear.
In the present study, we report the differential susceptibility of the heart to pressure overload of 2 inbred strains of rats, the development of which has allowed us to perform a genetic study that implicates the cardiac ryanodine Ryr2 receptor in the hypertrophic response of the RV to hypoxia-induced pulmonary hypertension.
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Methods |
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Animals and Genetic Crosses
Inbred Wistar-Kyoto rats (WKY, Charles River, UK) and Fischer 344 (F344) rats (Olac, UK) were used. Reciprocal mating of the parental strains, WKY (male)xF344 (female) and WKY (female)xF344 (male), produced the first-generation F1 hybrid animals, and brother-to-sister mating produced an F2 segregating generation. Male F2 progeny (n=130) were selected for genotype and phenotype analysis. This number of animals is sufficient to detect 4 quantitative trait loci (QTLs) of additive effect (each explaining one fourth of the difference in RV weight between the WKY and F344 lines) with 80% power when all the progeny are genotyped and interval mapping is used to analyze the data.6
Animals were fed a regular diet (3.3% fat, 21.3% protein, and 58% carbohydrate) and maintained at a constant temperature (20°C to 22°C) with a 10-hour on/14-hour off light cycle. All procedures were conducted in accordance with Imperial College of Science, Technology, and Medicine guidelines.
Phenotyping Procedure
Male rats aged 12 weeks were placed in a normobaric
hypoxic chamber for 21 days.7
Mean pulmonary artery pressure and systemic blood pressure were
measured in the anesthetized animal (pentobarbital sodium, 60 mg/kg IP)
via cannulas placed in the pulmonary artery (via the right jugular
vein) and left carotid artery,
respectively.8 Arterial blood
was taken for estimation of hematocrit before the hearts were removed
and blotted. The RV was dissected free and weighed. The LV and septum
were weighed together.
Genomic DNA Preparation
The liver and the kidneys were snap-frozen in liquid
nitrogen and stored at -80°C until genomic DNA was extracted by use
of a Nucleon genomic DNA extraction kit
(Scotlab).
Genotyping
Polymerase chain reaction (PCR) amplification was
used to genotype the F2 animals at 157
polymorphic microsatellite loci as described
before.9 The PCR primer pairs
(from Research Genetics or Genosys Biotechnologies) produced products
that differed by >5 bp between the 2 strains, and the PCR conditions
were optimized to permit visualization of the specific PCR products
with ethidium bromide after electrophoretic separation through 4%
agarose gels (3:1 NuSieve:agarose,
Flowgen).9
In the primary screen, 55 F2 animals constituting the top and bottom quartiles of the cumulative frequency distribution of RV weight were genotyped across all the autosomes. The remaining 76 F2 animals were then genotyped by using markers for regions showing evidence of linkage (lod score >1.5) in the primary screen.
Linkage and Statistical Analysis
The statistical significance of an interstrain
difference in parental phenotype was determined by the Mann-Whitney
U test. The significance level
was set at P<0.01.
The Mapmaker/EXP 3.0 and Mapmaker/QTL 1.1 computer packages were used to construct genetic linkage maps and to localize QTLs relative to the position of the microsatellite markers.10 Maximum lod scores supporting the presence of a QTL at each 1-cM interval along the genetic map were computed by assuming either a free, additive, dominant, or recessive mode of inheritance. The lod scores were then represented graphically in relation to chromosome position. In addition, an estimate of the fraction of the total variance explained by a particular QTL was obtained. The effect on the RV weight of alleles at the marker locus associated with the highest lod score was evaluated by 1-way ANOVA. To reduce type 1 errors, the lod score thresholds for significant linkage were set as follows: free genetics model, 4.3; dominant and recessive models, 3.4; and codominant model, 3.3.11 These thresholds correspond to a 0.05 probability of a false-positive in a genome scan.
Somatic Cell Hybrid and FISH Analysis
A panel of 15 (ratxmouse) somatic cell hybrids
segregating rat chromosomes was used as described
previously12 with the use of
Southern blotting with a 0.76-kb cDNA probe derived from rat Ryr2 mRNA
(gift from Prof F.A. Lai, University of Wales College of Medicine,
Cardiff) to detect the Ryr2
gene.
Fluorescence in situ hybridization (FISH) was performed as described elsewhere.13 A 287-bp biotin-labeled probe was generated by PCR with use of the cloned cDNA as template and the following primers: forward 5'-GAGACAGAATCAGCGAGTTAC and reverse 5'-GAGGACAGGATAGTTCTCAAG.
Ryanodine Binding Studies
Sarcoplasmic membranes were prepared by homogenizing,
on ice, the free wall of the RVs from individual normoxic rat hearts.
The binding protocol was a modification of one described
previously.14 Cardiac
homogenate proteins (230 µg) were incubated for 60 minutes at 37°C
with 0.1 to 50 nmol/L
[9,21(n)-3H]ryanodine (specific activity
1.85 to 3.7 TBq/mmol, 7.4 MBq/mL; Amersham Pharmacia Biotech) in 1 mL
binding buffer containing 1 mol/L KCl, 25 mmol/L HEPES (pH 7.2), 0.3
mol/L sucrose, 0.1 mg/mL BSA, 1 mmol/L ATP, and 100 µm/L
CaCl2. To compare ryanodine binding sites
in WKY and F344 hearts, we used the [Ca2+]
(10-1 mmol/L) that gave the highest
Bmax in preliminary experiments. Nonspecific
binding was determined in the presence of a 1000-fold excess of
unlabeled ryanodine (Sigma). The incubations were terminated by adding
5 mL ice-cold buffer, followed by rapid filtration through Whatman GF-B
glass-fiber filters presoaked in 4% polyethyleneimine. Each filter was
washed 3 times with 5 mL ice-cold buffer and air-dried. The
radioactivity remaining on the filter was determined with use of an LKB
liquid scintillation counter.
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Results |
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Hypoxia-Induced Pulmonary Hypertension and RV Hypertrophy
Adult WKY and F344 rats have similar pulmonary artery pressures at rest when breathing air, but WKY have a lower systemic blood pressure and a greater cardiac mass (Table 1
). Exposure to hypoxia
(FIO2
10%) for 21 days was associated with an increase in mean pulmonary
artery pressure and RV weight in both strains but significantly more in
the WKY strain. LV mass also increased more in the WKY strain despite a
further fall in systemic blood pressure
(Table 1). However, the LV measurement included the septum,
which hypertrophies with the RV. Histology of the hypertrophied
ventricles shows that the main cellular change is myocyte hypertrophy
rather than proliferation of nonmyocyte cells or excessive collagen
deposition (data not shown). The rise in hematocrit was the same in the
2 strains, making it unlikely that the strain difference is due to
variation in oxygen sensing.
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We examined the following phenotypes in a WKYxF344 intercross: (1) RV weight, (2) RV/body weight ratio, (3) RV weight/LV weight ratio, (4) LV weight alone, and (5) pulmonary artery pressure. Because the septum hypertrophies as part of the RV response, expressing RV as a ratio of LV+septum weight reduced the interstrain differences in RV hypertrophy. For these reasons and because the animals were all studied at the same age, we focused on uncorrected RV weight.
F1 (n=27) and male
F2 (n=130) animals from a WKYxF344 intercross
showed an intermediate rise in pulmonary artery pressure and RV mass
compared with the parental strains
(Figure 1). The average of the phenotypic variances of the 3
nonsegregating generations (WKY, F344, and F1)
was used to estimate the environmental variance of RV weight. The
proportion of the total F2 variance that was due
to genetic variation, expressed as heritability, was calculated
according to the following formula: (total F2
variance-environmental variance)x100/total F2
variance; the result was found to be 64%. Comparison of the variances
in the segregating generations with those in the nonsegregating
generations6 indicated the
involvement of at least 3 or 4 genes in the interstrain difference of
the hypertrophic response of the RV.
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Linkage of RV Weight to Rat Chromosome 17
QTL
A genetic linkage map for each of the 20 rat autosomes
was constructed with genotypic data from the male
F2 rats and a panel of 157 polymorphic
microsatellite markers (the X and Y chromosomes were not screened). The
best map order for the markers was determined by multipoint linkage
analysis, and the genetic distances between markers were calculated by
using the Haldane mapping function. We estimate that our markers cover
>99% of the rat autosomes on the basis of the recent reevaluation of
the genome size, with an average intermarker distance of 20
cM.9
A genetic linkage map for rat chromosome 17 was generated
with the data from 15 markers for all 130 F2
progeny. Using the Mapmaker/QTL program, we found a QTL on rat
chromosome 17 that had a major affect on RV weight
(Figure 2). This QTL was supported by a lod score of 6.5,
accounted for 22% of the total variance of RV weight in the
F2 population, and was independent of pulmonary
artery pressure (lod score 1.6). The peak was centered over the marker
D17rat41, close to Chrm3, with
a 1-lod support interval of 5 cM. The linkage persisted when RV weight
was expressed as a ratio of body weight (lod score 4.5) to LV+septum
weight (lod score 3.7).
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The results of 1-way ANOVA of the cosegregation of RV weight
with D17Rat41 are shown in
Table 2. This locus appears to affect RV weight in a
dominant fashion, inasmuch as the F2 animals
homozygous for the WKY (WW) or F344 (FF) allele had the largest and
smallest mean RV weights, respectively, and the mean values for the
heterozygotes (WF) were indistinguishable from those of the homozygous
F344 group. Rats homozygous for the WKY allele at the marker D17Rat41
have a RV weight 
52.4 mg greater than those homozygous for the F344
allele (P<0.001).
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No other QTLs for RV weight and no QTLs for LV weight or
pulmonary artery pressure were identified in this cross that met our
stringent criteria (see Linkage and Statistical Analysis)
(Figure 3). Even though the maximal distance between markers
was never >31 cM, it is possible that we may have missed genetic
factors with an autosomal-recessive or sex-linked pattern of
inheritance or autosomal-dominant loci of small
effect.
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Localization of Ryr2 to Rat Chromosome
17
Inspection of the mouse and human genetic maps
homologous to our QTL on rat chromosome 17 suggested that
Ryr2, the gene encoding the
cardiac form of the ryanodine receptor, is in the region of interest.
The rat Ryr2 gene was first
assigned to this rat chromosome by using a panel of 15 (ratxmouse)
somatic cell hybrids segregating rat chromosomes. A 0.76-kb rat Ryr2
cDNA probe detected 6 fragments when rat genomic DNA was digested with
the restriction enzyme PstI
(5.0, 4.2, 3.5, 3.0, 2.6, and 1.7 kb) (data not shown). The 2 most
intense bands (5.0 and 3.5 kb), as well as the 2.6- and 1.7-kb bands,
were easily distinguishable from the bands obtained with digested mouse
genomic DNA (8.9, 8.1, 5.8, 4.2, 4.0, and 2.8 kb). The 4 unique rat
fragments segregated together with rat chromosome 17 (data not shown),
as did other genes previously assigned to this chromosome, eg,
Chrm3 (17q12.1) and
Tpl2
(17q12.1-q12.2).15 16
To confirm the position of Ryr2
within rat chromosome 17, FISH was performed with the use of a
biotin-labeled 289-bp rat Ryr2 cDNA probe. Double spots (2 labeled
sister chromatids) were found only on rat chromosome 17
(Figure 4). The fluorescent signals were located in the
distal half of 17q, namely, in the region 17q12.2-q12.3. Because the
human homologues CHRM3,
RYR2, and
TPL2 are separated
(CHRM3 and
RYR2 map to human chromosome
1,17 18 whereas
TPL2 maps to human chromosome
1019 ), the most likely order
of the rat genes on rat chromosome 17 is as follows:
17qcentr-Chrm3-Ryr2-Tpl2-17qtel.
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Ryanodine Binding Studies
To explore the role of Ryr2 in our rat cross, we looked
for evidence of a difference in functional expression of this channel
in the 2 strains. Ryr2 is the predominant form of the ryanodine
receptor in myocardium.14
Therefore, we performed ligand-binding studies with the use of
[3H]ryanodine and homogenates of the RV
containing sarcoplasmic reticular membranes. There was a significant
21% reduction in Bmax for ryanodine binding to
cardiac membranes from normal WKY compared with F344 animals, with no
significant difference in
Kd
(Figure 5).
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Discussion |
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QTLs contributing to the regulation of adult cardiac mass and blood pressure have been reported on several rat chromosomes, including 1,20 3,21 and 8.22 In these cases, the cardiac mass phenotype may be acting as a surrogate for the pressure load. On the other hand, genetic loci for cardiac mass that are independent of the influence of blood pressure have been found on rat chromosomes 2,20 3,9 10,23 12,24 25 and 17.26 The latter QTL was close to the Edn1 and Drd1A genes on the short arm of rat chromosome 17 (17p14), at least 40 cM away from the QTL we describe in the present study. It is important to emphasize that none of the above studies provided substantive evidence of functional differences or genetic sequence variation implicating a particular gene in the control of cardiac mass.
Genetically determined variation in the cardiovascular response to hypoxia is well documented in animals and humans, but few attempts have been made to elucidate the genetic basis of the differential response to hypoxia. In the only study published to date, a locus on rat chromosome 1 cosegregates with RV weight and pulmonary artery systolic pressure in a (fawn-hoodedxF344)F1xfawn-hooded backcross.27 We did not detect a significant QTL on rat chromosome 1 in the present study.
Several lines of evidence make an abnormality of Ryr2 receptor activity an attractive candidate for the differential hypertrophic response observed between the WKY and F344 strains. This receptor plays an essential role in excitation-contraction coupling by releasing Ca2+ ions from the sarcoplasmic reticulum after stimulation by calcium ions entering through the dihydropyridine receptor.28 Furthermore, perturbations of Ryr2 function have already been linked with myocardial hypertrophy. In pressure overload–induced cardiac hypertrophy in several species, including the rat, there is a reduction of receptor density and Ryr2 mRNA that correlates with a decrease in Ca2+ transient.29 30 However, it has been unclear whether these changes are primary events or a consequence of the hypertrophic process. In support of the former is the observation that administration of FK-506 (tacrolimus), an immunosuppressant that binds to FKBP12.6, has been associated with the development of hypertrophic cardiomyopathy in children.31 32 FKBP12.6 itself is known to bind to and modulate channel gating of the Ryr2 receptor.33 34 Knockout mice lacking either FKBP12 or Ryr2 die during embryogenesis,35 36 principally because of disruption of heart tube development.
In conclusion, we have described segregation and linkage data that implicate a gene on rat chromosome 17 in the hypertrophic response of the RV to hypoxia-induced pulmonary hypertension. We have also presented the first evidence that Ryr2 is in the vicinity of the QTL, and we clearly demonstrate a difference between F344 and WKY in the binding of [3H]ryanodine to myocardial homogenates. Significantly, these differences in binding are evident before exposure to hypoxia. It is of considerable interest that our previous study examining the genetic factors controlling normal cardiac mass in these 2 strains identified a QTL on rat chromosome 3 but not on chromosome 17,9 highlighting the differences between the genetic mechanisms controlling normal cardiac growth and pathological hypertrophy. It is interesting to speculate that the greater cardiac hypertrophy in the WKY strain results from an attempt of cardiac myocytes to compensate for a lower abundance of ryanodine receptors compared with those in the myocardium of F344 rats. If true, mechanisms to improve cardiac Ryr2 activity and increase contractile efficiency may, paradoxically, reduce the stimulus to hypertrophy and the potential to develop cardiac failure.
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Acknowledgments |
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This work was supported by the British Heart Foundation (PG95170 and PG98018), the European Commission (ERBBIO4CT960562), and the Fund for Medical Scientific Research (FRSM, Belgium). C.S. Haley acknowledges support from the Biotechnology and Biological Sciences Research Council. C. Szpirer is a Research Director of the Fonds National de la Recherche Scientifique (Belgium). We thank M. Rivière and P. Van Vooren for excellent technical assistance with the somatic cell hybrid and FISH studies. We are grateful to Prof F.A. Lai (University of Wales College of Medicine, Cardiff) for the gift of the rat Ryr2 cDNA probe and for helpful discussions.
Received March 13, 2000; revision received July 17, 2000; accepted July 28, 2000.
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