© 1999 American Heart Association, Inc.
Rapid Communication |
Cosegregation Analysis in Genetic Crosses Suggests a Protective Role for Atrial Natriuretic Factor Against Ventricular Hypertrophy
From the Neurobiology and Vasoactive Peptides Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada.
Correspondence to Christian Deschepper, MD, Neurobiology and Vasoactive Peptides, Clinical Research Institute of Montreal (IRCM), 110 Pine Ave West, Montréal, Québec, Canada, H2W 1R7. E-mail deschec{at}ircm.qc.ca
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Abstract |
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Abstract—In most rat models studied to date, increased ventricular mass is associated with high ventricular expression of the atrial natriuretic factor (ANF) gene. However, it is unknown whether ANF plays a beneficial or detrimental role in the course of left ventricular hypertrophy or whether ANF gene expression could be genetically linked to cardiac mass. To address such questions, we performed a cosegregation analysis in genetic crosses of inbred strains of rats. To select strains with the appropriate phenotypic characteristics, we first compared the ventricular abundance of ANF mRNA to ventricular mass (corrected for body weight) in 2 recombinant inbred strains derived from Wistar-Kyoto (WKY)/spontaneously hypertensive rat (SHR) hybrid crosses, ie, WKY-derived hyperactive (WKHA) and WKY-derived hypertensive (WKHT) rats, as well as in their parental inbred strains. In the 2 such strains that were normotensive, we observed that ventricular mass was higher in WKHA than in WKY rats, yet ventricular ANF mRNA was less abundant in WKHA than in WKY rats. Within a segregating population of F2 animals generated from a cross between WKY and WKHA genitors, the abundance of ventricular ANF mRNA and peptide correlated inversely with left ventricular mass, in contrast to the positive correlation observed with ß-myosin heavy chain mRNA. Finally, in the equally hypertensive SHR and WKHT strains, we found that ventricular mass was higher in SHR than in WKHT, yet ventricular ANF mRNA was less abundant in SHR than in WKHT. These results demonstrate for the first time that low ventricular ANF gene expression can be linked genetically to high cardiac mass independently of blood pressure and are consistent with a protective role for ANF against left ventricular hypertrophy.
Key Words: hypertrophy, left ventricular • atrial natriuretic factor • rat, inbred strain • model, genetic • gene expression
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cardiovascular diseases are the principal cause of mortality and morbidity in industrialized countries. In recent years, left ventricular hypertrophy (LVH) has emerged as a powerful independent risk factor for cardiovascular mortality and morbidity.1 2 To gain further knowledge about the causes and consequences of this condition, experimental animal models of LVH have been created either in rats3 4 5 6 7 8 or in several models of transgenic mice.9 10 11 12 13 Among other things, such models have made it possible to discover some of the biochemical alterations that typically associate with LVH, among which increased ventricular expression of atrial natriuretic factor (ANF) has emerged as one of the most consistent features.3 4 5 6 7 8 9 10 11 12 13 Despite the tight association between ANF and experimentally induced LVH, several questions have remained unanswered. First, it is not known whether ventricular ANF plays any role in the course of LVH and whether such role would be beneficial or detrimental. Second, in all models of LVH where an increase of ventricular ANF has been reported, LVH resulted from the imposition of an exogenous stimulus. However, how ventricular ANF correlates with ventricular mass in the absence of increased workload and/or alteration of intracellular cardiac signaling is not known. This particular question is important in light of evidence showing either in rats14 15 16 17 18 or humans19 20 that factors other than blood pressure or workload may affect the development of LVH. It is pertinent to ask whether ventricular ANF may be one such factor and in which way it could affect cardiac mass.
We reasoned that cosegregation analyses in genetic crosses of inbred rats would provide a way to investigate whether there was a genetic link between ventricular ANF expression and cardiac mass. Ideally, we would need strains displaying quantitative differences in the abundance of ventricular ANF mRNA and in cardiac mass but no differences in terms of blood pressure. Some novel recombinant inbred rat strains that had been created from the progeny of F2 crosses of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) constituted attractive candidates in this regard.21 22 The WKY-derived hyperactive (WKHA) strain is normotensive and exhibits increased behavioral activity in a novel environment as well as increased cardiovascular reactivity to stress compared with WKY rats, and its cardiac mass is higher than that of WKY.21 22 23 Conversely, the WKY-derived hypertensive (WKHT) strain is hypertensive, its behavioral activity and cardiovascular reactivity to stress are not increased compared with WKY rats, and its cardiac mass is intermediary between that of WKY and SHR.21 22 23 It has been verified that the WKHA and WKHT strains are truly inbred and that their genome truly represented mixes of the genomes of WKY and SHR.22 However, there is no information on the ventricular abundance of ANF or other biochemical markers of LVH in these various strains. We therefore performed a systematic phenotypic characterization of these various strains to test whether some of them might be suitable for investigations involving genetic crosses.
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Materials and Methods |
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Animals
Male SHR/Cr and WKY/Cr rats were obtained from Charles River (St-Constant, Québec, Canada) and are hereafter designated SHR and WKY. Male WKHA/Cfd and WKHT/Cfd were obtained from the colony that is maintained at the Institut de Recherches Cliniques de Montréal (IRCM). This colony was originated from breeding stock obtained from E.D. Hendley (Burlington, Vt) and has been registered with the Institute of Laboratory Animal Resources of the National Research Council.22 The strains are hereafter designated WKHA and WKHT.
Generation of F2 animals involved the mating of male WKHA to female WKY rats. The resulting F1 animals were mated again randomly to generate F2 animals, of which a total of 162 males were used at 12 weeks of age for the purpose of the present experiments.
Animal Procedures
Animal procedures were approved by the IRCM Animal Care
Committee and conducted according to the recommendations of the
Canadian Council on Animal Care. For each strain, 6 animals were
selected at the ages of 9, 12, 16, and 24 weeks. F2 animals were killed
at the age of 12 weeks. One day before sacrifice, the animals were
prewarmed to 37°C and then placed in an acrylic restrainer to measure
systolic blood pressure by tail-cuff plethysmography.
On the day of tissue collection, each animal was first weighed for determination of whole-body weight. The rats were then killed by decapitation, the hearts were dissected out, trimmed at the atrioventricular junction, the ventricles were emptied of residual blood, and the block of tissue constituted by both ventricles was weighed to calculate the biventricular weight/body weight (VW/BW) ratio. For experiments performed on F2 animals, the ventricles were further dissected into right ventricle and left ventricle (which included the septal wall), and each part was weighed individually. The ventricles were further cut into pieces, frozen in liquid nitrogen, and kept at –70°C for further analysis.
RNA Analysis
Frozen fragments of tissue containing the free wall of the left
ventricle were pulverized with a mortar and pestle in liquid nitrogen,
and total RNA was extracted using a modification of the single-step
acid guanidium thiocyanate-phenol-chloroform
method.24 Northern blot analyses were performed
using the following probes: for ANF, the 800-bp
EcoRI-HindIII fragment from the SP64-rANF
plasmid25 ; for GAPDH, the 1.2-kb
EcoRI fragment from the American Type Culture Collection
78105 plasmid; for 
-myosin heavy chain (-MHC), the
oligonucleotide 5'-TTGTGGGATAGCAACAGCGA-3'; for
ß-myosin heavy chain (ß-MHC), the oligonucleotide
5'-GTCTCAGGGCTTCACAGG-3'; and for –skeletal actin, the
oligonucleotide 5'-GCAACCATAGCACGATGGTC-3'. Sequences
for the oligonucleotides were as published
previously.5 The blots were hybridized to either cDNA
or oligonucleotide probes labeled with
[32P], similarly as previously
described.5 26 After washing, the hybridized blots were
exposed to a phosphorscreen cassette, and the signals were
visualized and quantified using the ImageQuant software (Molecular
Dynamics, Sunnyvale, Calif). Results were normalized by dividing the
value for each sample by the intensity of either the corresponding 18S
ribosomal band or the signal obtained by hybridization with the GAPDH
probe. Comparisons between strains were performed by dividing each
individual value by the mean of the values obtained for the samples of
WKY rats of the same age group. Quantification of specific mRNAs in
hearts from F2 animals required distributing the samples over 11
different blots. In these cases, the values were further normalized by
including in each blot 2 samples of total RNA extracted from the
ventricle of one reference WKY rat and dividing each specific ratio
value by the mean value of the ratios obtained for the reference WKY
samples from the same blot.
ANF Radioimmunoassay
Fragments of left ventricular apex (±200 mg) were
weighed, powdered under liquid nitrogen, and boiled for 5 minutes in a
volume of 2 mL of 0.2 mol/L acetic acid. The extracts were then
centrifuged at 30 000g for 30 minutes. Aliquots of
5 µL of supernatant were assayed, using the same procedures and
reagents as described previously.27
Statistical Analysis
Data sets collected in different strains at different ages were
analyzed by 2-way ANOVA, which tested the effect of strain, the
effect of age, and whether there was an interaction between both
factors. When significant differences were found, subsets of data were
further tested by post hoc Fisher least-significance difference (LSD)
tests. When comparisons were made between 2 groups, differences were
analyzed by Student t test. Linear regression
analysis was used to calculate the coefficient of correlation
(r) between left ventricular weight and other
variables; the level of significance of the correlation was then
calculated by ANOVA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 1
shows a
representative example of ANF Northern
analysis. This particular blot contains total RNA samples
obtained from the left ventricle of all 4 strains of rats killed at 16
weeks of age. Although the intensity of the 18S ribosomal bands was
comparable in all 4 groups, there were readily detectable differences
in the intensity of the ANF signal of all 4 groups, the relative
order of intensity being WKHA < WKY < SHR < WKHT.
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Additional measurements were performed first with WKY and WKHA rats at
9, 12, 16, and 24 weeks of age (Figure 2). Systolic blood pressure was
identical in both strains (Figure 2A); no difference was
detected by 2-way ANOVA. Comparisons of the VW/BW ratios (Figure 2B) across ages revealed that relative ventricular
mass was significantly higher (P<0.001) in WKHA than in WKY
rats, whereas there was no significant effect of age. The relative
abundance of ventricular ANF mRNA (Figure 2C) was
inverse to what had been observed with VW/BW values: ANF mRNA was
significantly lower (P<0.001) in WKHA than in WKY rats,
with no effect of age.
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Differences in ANF mRNA concentration were mirrored at the level of ANF
peptide; the left ventricular concentration of ANF
immunoreactivity in WKHA rats was about 30% of the levels found in WKY
rats (Table 1). Moreover, it was found by
Northern blot analysis that the abundance of ß-MHC and
-skeletal actin mRNAs was significantly higher in WKHA than in WKY
rats, whereas there were no quantitative changes in the abundance of
-MHC mRNA (Table 1).
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To test whether low abundance of ventricular ANF mRNA
and/or peptide would segregate with high ventricular mass
in a genetic cross, we measured both variables in rats originating
from a population of 162 male hybrid WKHA/WKY crosses. In these
experiments, we measured left ventricular (instead of
biventricular) weight, because parallel experiments had
revealed that the ventricular weight difference between
WKHA and WKY rats could be entirely accounted for by differences in the
weight of left ventricles. Within the context of this segregating F2,
we observed that the left ventricular concentrations of ANF
mRNA and ANF peptide correlated inversely with left
ventricular mass (Figure 3).
In contrast, the concentration of ß-MHC RNA increased proportionately
with left ventricular mass (Figure 3). Linear
regression analysis of the points from these data sets
confirmed that all 3 correlations were statistically significant (Table 2). Skeletal actin mRNA also tended to
increase with left ventricular mass, but the association
failed to reach statistical significance. Of note, the number of points
analyzed did not always correspond exactly to the entire number
of animals generated for the F2 population. For instance, there was not
always enough ventricular tissue left for some animals from
the F2 population to measure ANF immunoreactivity. In the Northern blot
experiments, some membranes presented background problems that
prevented accurate quantification of the corresponding
autoradiograms.
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Other comparisons were made between WKHT rats and SHR, which are both
hypertensive (Figure 4A). The 2-way ANOVA
revealed that systolic blood pressures from WKHT rats were not
statistically different from that of SHR but that blood pressures
increased significantly in both strains as a function of age
(P<0.001). Comparisons of the VW/BW ratios (Figure 4B) across ages revealed that ventricular mass was
significantly higher in SHR than in WKHT rats (P<0.0011)
but that age had no significant effect. Similarly to what had been
observed for the 2 normotensive strains, the relative abundance of
ventricular ANF mRNA (Figure 4C) was inverse to what
had been observed with VW/BW values: ANF mRNA was significantly lower
in SHR than in WKHT rats (P<0.0038).
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Discussion |
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Cardiac atria are the predominant source of production of circulating ANF. The canonical role of this hormone is to promote natriuresis by regulating renal blood flow and exerting a concerted action on several nephron segments.28 Natriuretic peptides are also produced in fetal and neonatal ventricles, but their production greatly decreases during the postnatal period, and by the time the animal reaches adult age, ANF mRNA is much less abundant in ventricles than in atria.25 Whereas ventricular ANF may increase when maneuvers are performed to induce LVH, it is not known whether it plays a particular role, if any, in the course of LVH, and whether such role would be beneficial or detrimental.
The availability of the WKHA inbred rat strain provided us with the opportunity to test whether ventricular ANF could be genetically linked to ventricular mass. WKHA and WKY rats are both normotensive, and ventricular mass is higher in WKHA than in WKY, yet ventricular ANF mRNA was consistently lower in WKHA than in WKY. Differences in ANF mRNA were mirrored by changes in the ventricular concentration of ANF peptide. Expression of the ANF gene in the ventricle may be governed by both mechanical and local humoral influences.29 Given that the WKHA and WKY rats are both normotensive, it is unlikely that mechanical forces would be responsible for differences between the 2 strains.
Within the particular context of an F2 WKHA/WKY hybrid cross (where each individual animal has a unique and distinct genetic background), we found that low abundance of ventricular ANF (either peptide or mRNA) correlated with high ventricular mass. This finding is in contrast with previous reports, in which LVH had consistently been found to be accompanied by increases in the abundance of ANF mRNA.3 4 5 6 7 8 9 10 11 12 13 Alternatively, one might conceive that enlarged ventricular walls in the absence of increased workload could reduce ventricular ANF via a reduction of wall stress. However, if this were the case, other markers of LVH would be expected to decrease as well. Our observations of ß-MHC suggest the opposite. Furthermore, ventricular ANF has also been reported to be increased in exercised-induced LVH, which is also characterized by enlarged ventricular walls and reduced wall stress.30 31 This suggests that ANF ventricular expression is not always simply a reflection of wall stress.
One other explanation can be derived from recent data concerning the actions of ANF on cardiocytes. Ventricular cardiomyocytes constitute a legitimate target of natriuretic peptides, since they have been reported to contain the natriuretic peptide receptors NPR-A and NPR-B, and isolated myocytes produce cGMP when exposed to ANF or brain natriuretic peptide (BNP).32 Both natriuretic peptides and cGMP (the presumed second messenger mediating most of the biological actions of natriuretic peptides28 ) have been shown to have a variety of effects on cardiomyocytes, as they improve the relaxation properties of these cells, increase their susceptibility to arrhythmias, stimulate their rate of glycolysis, and reduce activity of L-type Ca2+ channels.33 34 35 36 Furthermore, Yamamoto et al37 have recently used in vivo inhibitors of the intracardiac endogenous natriuretic peptide system to show that local natriuretic peptides may have autocrine-paracrine roles in the regulation of ventricular function. In vitro, several investigators have shown recently that ANF and/or cGMP have antigrowth effects on either neonatal cardiomyocytes or cardiac fibroblasts in culture.38 39 40 Finally, some investigators have produced mice in which the genes of either ANF or its corresponding receptor have been invalidated.41 42 In both cases, there is an increase in cardiac mass that is disproportionately large in comparison with the very modest increases in blood pressure found in these animals.
In light of such data, the action of ANF and/or cGMP may well be to protect the heart against hypertrophy. When LVH results from exogenous stimuli, ventricular ANF may increase as a counterregulatory mechanism to the stimulus. In contrast, when the relative amount of baseline ventricular ANF is decreased, there may be increased susceptibility to LVH. If this hypothesis is correct, one might predict that with a given level of increased blood pressure, the severity of LVH will be inversely proportional to the amplitude of the ventricular ANF response. Although we have not performed experiments addressing this question with WKHA rats, the data we have obtained in WKHT rats and SHR are suggestive in this regard. Indeed, both strains are equally hypertensive, and in both strains, ventricular ANF mRNA is higher than in normotensive WKY rats. However, the abundance of ventricular ANF mRNA is consistently higher in WKHT rats than in SHR, yet ventricular mass is lower in WKHT than in SHR. At the very least, this observation provides yet another novel example of when the magnitude of the LVH process can be dissociated from that of the ventricular ANF response. However, it also suggests that beyond baseline levels (as illustrated in WKHA and WKY rats), the amplitude of the ventricular ANF response (which is genetically determined) may also modulate the importance of the hypertrophic process to exogenous stimuli, ie, the environment.
In summary, we found by cosegregation analysis in genetic crosses that there was a genetic link between low ventricular ANF mRNA and high ventricular mass. Combined with recent reports indicating that ANF and/or cGMP may have antigrowth effects, our data are consistent with a protective role for endogenous ventricular ANF against LVH. This hypothesis is also compatible with experiments in SHR, showing that treatments that increase the ventricular concentration of ANF and/or cGMP also decrease LVH in the absence of any detectable effect on blood pressure.43 44 However, it is not possible to determine in these experiments whether the treatments affected cardiac mass by a direct effect on the ventricles or via peripheral effects. In future experiments, it will therefore be worthy to explore whether ventricular ANF may affect ventricular mass directly via local effects and to decipher the mechanisms of such actions.
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Acknowledgments |
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This work was supported by a group grant (GR-13922) of the Canadian Medical Research Council (MRC) to the Multidisciplinary Research Group on Hypertension and a grant from the Fondation des Maladies du Coeur du Québec (to C.F.D.). C.F.D. is supported by the Fonds de la recherche en santé du Québec as chercheur-boursier senior. We are grateful to Dr Timothy L. Reudelhuber for constant support and insightful comments throughout the course of the present study.
Received February 16, 1999; accepted April 16, 1999.
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 K. R. Johnson and K. R. Olson Responses of the trout cardiac natriuretic peptide system to manipulation of salt and water balance Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1170 - R1179. [Abstract] [Full Text] [PDF]
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 S J. Sangaralingham, M Y. Tse, and S. C Pang Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice J. Endocrinol., July 1, 2007; 194(1): 143 - 152. [Abstract] [Full Text] [PDF]
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 B. M. Palmer, Z. Chen, R. R. Lachapelle, E. D. Hendley, and M. M. LeWinter Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H463 - H473. [Abstract] [Full Text] [PDF]
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 J. Dutil, V. Eliopoulos, E.-L. Marchand, A. M. Devlin, J. Tremblay, K. Prithiviraj, P. Hamet, A. Migneault, D. deBlois, and A. Y. Deng A quantitative trait locus for aortic smooth muscle cell number acting independently of blood pressure: implicating the angiotensin receptor AT1B gene as a candidate Physiol Genomics, May 11, 2005; 21(3): 362 - 369. [Abstract] [Full Text] [PDF]
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E. A. Aiello, M. C. Villa-Abrille, E. M. Escudero, E. L. Portiansky, N. G. Perez, M. C. Camilion de Hurtado, and H. E. Cingolani Myocardial hypertrophy of normotensive Wistar-Kyoto rats Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1229 - H1235. [Abstract] [Full Text] [PDF]
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 T. Mori, Y.-F. Chen, J. A. Feng, T. Hayashi, S. Oparil, and G. J Perry Volume overload results in exaggerated cardiac hypertrophy in the atrial natriuretic peptide knockout mouse Cardiovasc Res, March 1, 2004; 61(4): 771 - 779. [Abstract] [Full Text] [PDF]
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 A. Zahabi, S. Picard, N. Fortin, T. L. Reudelhuber, and C. F. Deschepper Expression of Constitutively Active Guanylate Cyclase in Cardiomyocytes Inhibits the Hypertrophic Effects of Isoproterenol and Aortic Constriction on Mouse Hearts J. Biol. Chem., November 28, 2003; 278(48): 47694 - 47699. [Abstract] [Full Text] [PDF]
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 C. F. Deschepper, I. Boutin-Ganache, A. Zahabi, and Z. Jiang In Search of Cardiovascular Candidate Genes: Interactions Between Phenotypes and Genotypes Hypertension, February 1, 2002; 39(2): 332 - 336. [Abstract] [Full Text] [PDF]
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J. R. Klinger, R. R. Warburton, L. Pietras, P. Oliver, J. Fox, O. Smithies, and N. S. Hill Targeted disruption of the gene for natriuretic peptide receptor-A worsens hypoxia-induced cardiac hypertrophy Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H58 - H65. [Abstract] [Full Text] [PDF]
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 G. Foldes, M. Suo, I. Szokodi, Z. Lako-Futo, R. deChatel, O. Vuolteenaho, P. Huttunen, H. Ruskoaho, and M. Toth Factors Derived from Adrenals Are Required for Activation of Cardiac Gene Expression in Angiotensin II-Induced Hypertension Endocrinology, October 1, 2001; 142(10): 4256 - 4263. [Abstract] [Full Text] [PDF]
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 G. Schwartzbauer and J. Robbins Matters of Sex: Sex Matters Circulation, September 18, 2001; 104(12): 1333 - 1335. [Full Text] [PDF]
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M. van Eickels, C. Grohe, J. P.M. Cleutjens, B. J. Janssen, H. J.J. Wellens, and P. A. Doevendans 17{beta}-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy Circulation, September 18, 2001; 104(12): 1419 - 1423. [Abstract] [Full Text] [PDF]
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 A. Zahabi and C. F. Deschepper Long-chain fatty acids modify hypertrophic responses of cultured primary neonatal cardiomyocytes J. Lipid Res., August 1, 2001; 42(8): 1325 - 1330. [Abstract] [Full Text] [PDF]
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 C. F. Deschepper, S. Masciotra, A. Zahabi, I. Boutin-Ganache, S. Picard, and T. L. Reudelhuber Functional Alterations of the Nppa Promoter Are Linked to Cardiac Ventricular Hypertrophy in WKY/WKHA Rat Crosses Circ. Res., February 2, 2001; 88(2): 223 - 228. [Abstract] [Full Text] [PDF]
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O. Lisy, M. M. Redfield, S. Jovanovic, M. Jougasaki, A. Jovanovic, H. Leskinen, A. Terzic, and J. C. Burnett Jr Mechanical Unloading Versus Neurohumoral Stimulation on Myocardial Structure and Endocrine Function In Vivo Circulation, July 18, 2000; 102(3): 338 - 343. [Abstract] [Full Text] [PDF]
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L. G. MELO, M. E. STEINHELPER, S. C. PANG, Y. TSE, and U. ACKERMANN ANP in regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models Physiol Genomics, June 29, 2000; 3(1): 45 - 58. [Abstract] [Full Text] [PDF]
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C. F. Deschepper, S. Picard, G. Thibault, R. Touyz, and J.-L. Rouleau Characterization of myocardium, isolated cardiomyocytes, and blood pressure in WKHA and WKY rats Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H149 - H155. [Abstract] [Full Text] [PDF]
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