EXPERIMENTAL STUDIES
Gender differences in molecular remodeling in pressure overload hypertrophy
Ellen O. Weinberg, PhDa,
Christiane D. Thienelt, MDa,
Sarah E. Katz, BAa,
Jozef Bartunek, MDa,
Minori Tajima, MD, PhDa,
Susanne Rohrbacha,
Pamela S. Douglas, MD, FACCa and
Beverly H. Lorell, MD, FACCa
a Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory and the Department of Medicine (Cardiovascular Division) of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
Manuscript received June 4, 1998;
revised manuscript received February 23, 1999,
accepted March 24, 1999.
Reprint requests and correspondence: Dr. Ellen O. Weinberg, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, Massachusetts 02215
eweinber{at}caregroup.harvard.edu
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Abstract
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OBJECTIVES
The objective of this study was to examine gender differences in left ventricular (LV) function and expression of cardiac genes in response to LV pressure overload due to ascending aortic stenosis in rats.
BACKGROUND
Clinical studies have documented gender differences in the pattern of adaptive LV hypertrophy. Whether these differences result from intrinsic differences in molecular adaptation to pressure overload between men and women, or are related to other factors is not known.
METHODS
Male (n = 8) and female (n = 8) Wistar rats underwent ascending aortic stenosis and were studied 6 weeks after banding with gender-matched control rats (male n = 7; female n = 7). The LV contractile reserve was examined in isolated hearts from each group. We compared LV messenger ribonucleic acid (mRNA) levels of atrial natriuretic factor (ANF), beta-myosin heavy chain, sarcoplasmic reticulum Ca2+–adenosine triphosphatase (ATPase) and Na+–Ca2+ exchanger. Reverse transcriptase polymerase chain reaction was used to identify estrogen receptor transcript in cardiac myocytes and LV tissue.
RESULTS
The magnitude of LV hypertrophy (LVH) and systolic wall stress were similar in male and female animals with LVH. Male LVH hearts demonstrated a depressed contractile reserve; in contrast, contractile reserve was preserved in female LVH hearts. The expression of beta-myosin heavy chain and ANF mRNA was greater in male versus female LVH hearts. Sarcoplasmic reticulum Ca2+-ATPase mRNA levels were depressed in male LVH but not in female LVH compared with control rats, and Na+–Ca2+ exchanger mRNA levels were increased similarly in both male and female LVH hearts. Estrogen receptor transcript was detected in both adult male and female cardiac myocytes and LV tissue.
CONCLUSIONS
There are significant gender differences in the LV adaptation to pressure overload despite a similar degree of LVH and systolic wall stress in male and female rats. There is the potential for estrogen signaling through the adult myocyte estrogen receptor in both male and female rats to contribute to gender differences in gene expression in pathologic hypertrophy.
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Abbreviations and Acronyms
| | ANF | = atrial natriuretic factor | | cDNA | = complementary deoxyribonucleic acid | | LV | = left ventricular | | LVH | = left ventricular hypertrophy | | mRNA | = messenger ribonucleic acid | | PCR | = polymerase chain reaction | | RT | = reverse transcriptase | | SERCA-2 | = sarcoplasmic reticulum Ca2+–adenosine triphosphatase |
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Clinical studies have recently documented gender differences in the pattern of adaptive left ventricular (LV) hypertrophy (LVH) in response to increased afterload, such as occurs in aortic stenosis and hypertension. Cardiac performance is more frequently preserved in female compared with male patients with a similar degree of aortic stenosis and female patients more frequently demonstrate preserved or supernormal ejection parameters with small thick-walled chambers (1–5). The risk of adverse outcome in hypertensive patients associated with LVH is also influenced by gender (6,7). Whether these differences result from intrinsic differences in molecular adaptation to pressure overload between men and women, or are related to differences in age, degree of stenosis, underlying coronary artery disease, LV geometry per se or other factors extrinsic to the myocardium is not known.
We have extensively characterized the ascending aortic stenosis model of pressure overload LVH in male rats (8–15). Early after aortic banding in male rats, compensatory concentric hypertrophy is evident in conjunction with reexpression of LV hypertrophic genes, including beta-myosin heavy chain, alpha-skeletal-actin and atrial natriuretic factor (ANF). Later, a transition to failure becomes evident by depressed in vivo LV contractile indexes and progressive reduction in message levels of sarcoplasmic reticulum Ca2+–adenosine triphosphatase (SERCA-2) with persistent up-regulation of the hypertrophic gene program.
The objective of the present study was to determine whether there are differences between male and female rats in LV Ca2+-dependent contractile reserve and gene expression in response to chronic pressure overload in the absence of differences in age, duration and degree of aortic stenosis.
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Methods
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Preparation of animals.
Under anesthesia with intraperitoneal methohexital sodium (50 mg/kg), ascending aortic stenosis was created in male (n = 8) and female (n = 8) Wistar rats (70 to 90 g) obtained from Charles River Breeding Laboratories (Wilmington, Massachusetts), by placing a 0.56-mm internal diameter tantalum clip on the ascending aorta via a thoracic incision (LVH groups) as previously described (8–15). Body weights and age at the time of banding were similar in both groups. Additional male (n = 7) and female (n = 7) age-matched animals underwent sham operation to serve as controls (control groups). Animals were housed in a viral-antigen–free facility and were fed normal rat chow and water ad libitum. Animals were studied six weeks after aortic banding. The model is characterized by concentric LVH, the absence of chamber dilation and preserved ejection indexes at this stage after aortic stenosis in both male and female animals with LVH (11).
In vivo measurements.
Six weeks after banding, rats from each group underwent transthoracic echocardiographic and hemodynamic assessment for estimation of LV systolic meridional wall stress as previously described by our laboratory (8,9,11). Just before sacrifice, rats were anesthetized with intraperitoneal sodium pentobarbital (50 mg/kg) and in vivo LV systolic and diastolic pressures were obtained by closed chest LV catheterization as previously described by our laboratory (8–13,16). Left ventricular meridional systolic wall stress (kdyn/cm2) was estimated as: 0.334 x in vivo LV systolic pressure x (LVD/[1 + PWT/LVD]) where LVD = LV internal dimension and PWT = posterior wall thickness at end-systole. Left ventricular diastolic stress (kdyn/cm2) was estimated as 0.334 x in vivo LV diastolic pressure x (LVD/[1 + PWT/LVD]) where LVD = LV internal dimension and PWT = posterior wall thickness measured in centimeters at end-diastole. At the time of sacrifice, body weights were recorded and tibial lengths were obtained as indexes of growth.
Assessment of contractile reserve.
The isolated hearts were subjected to hemodynamic evaluation using the isovolumic buffer-perfused rat heart preparation as described in detail from our laboratory (8,10). In brief, hearts were rapidly removed and perfused with modified Krebs Henseleit buffer through a short cannula inserted into the aortic root just below the level of the clip. Coronary flow rate was adjusted to achieve a mean coronary perfusion pressure of 110 mm Hg in hearts from aortic stenosis rats and 75 mm Hg in hearts from control rats, and was then held constant, achieving comparable myocardial perfusion rates per gram of LV tissue in all groups (8,10). A collapsed latex balloon, slightly larger than the LV chamber, was placed in the LV and continuous LV pressure was measured via a Statham pressure transducer (Gould Instruments, Valley View, Ohio) connected to the balloon. Heart rate was held constant at 240 beats/min through external pacing (Grass Instruments, Quincy, Massachusetts). Temperature was maintained at 37°C.
At the end of a 20-min stabilization period, Ca2+-dependent contractile reserve was assessed as described by our laboratory (8,10,14,16). Left ventricular systolic pressure generation was measured at three perfusate calcium concentrations (0.6, 1.5 and 3.0 mmol/liter) at constant similar LV balloon volume. After hemodynamic evaluation, hearts were rapidly dissected into left and right ventricles, weighed, frozen in liquid nitrogen and stored at –80°C.
Analysis of LV messenger ribonucleic acid (mRNA) levels.
Total RNA was extracted from frozen LV tissue using TriReagent (Sigma, St. Louis, Missouri). For Northern blot analyses, 20 µg total RNA from individual LV samples was size-fractionated by electrophoresis in a 1.5% agarose-formaldehyde gel and transferred to a nitrocellulose membrane (Stratagene, La Jolla, California) by pressure transfer (Posiblot Pressure Blotter, Stratagene). The membrane was prehybridized for 10 min and hybridized with specific probes for 1 h in QuikHyb solution (Stratagene) at 65°C. After hybridization, the membrane was washed and exposed to Kodak (Rochester, New York) MR film for 0.25 to 3 days. The relative amounts of each mRNA were determined by densitometric analysis (Molecular Dynamics, Sunnyvale, California) and normalized to glyceraldehyde phosphate dehydrogenase. Stripping the membrane for reuse was performed following the manufacturer’s instructions (Stratagene). Probes used were the complementary deoxyribonucleic acid (cDNA) fragment encoding the SERCA-2 (provided by D. MacLennan), the cDNA fragment encoding the rat Na+–Ca2+ exchanger (provided by I. Komuro), the cDNA fragment encoding rat glyceraldehyde phosphate dehydrogenase, an 84-bp synthetic oligonucleotide complementary to the coding region of rat ANF and a 20-bp synthetic oligonucleotide complementary to the rat beta-myosin heavy chain gene. The cDNA fragments were radiolabeled with (gamma-32P) deoxycytidine triphosphate (New England Nuclear, Boston, Massachusetts) using random priming (Boehringer Mannheim, Indianapolis, Indiana), and the oligonucleotides were radiolabeled with (alpha-32P) adenosine triphosphate using T4 polynucleotide kinase.
Dissociation of LV myocytes.
Left ventricular myocyte isolation was performed as previously described (14–16). Rats were anesthetized with intraperitoneal pentobarbital (65 mg/kg body weight), and the heart was rapidly excised and attached to an aortic cannula. The heart was initially perfused with nominally Ca2+-free modified Krebs Henseleit buffer for 3 min. The heart was then perfused with recirculating buffer supplemented with 0.6 mg/ml collagenase (Class II, Worthington Biochemical Corp, Lake Wood, New Jersey), 0.04 mg/ml protease (Type XIV; Sigma) for 20 to 30 min. The heart was then removed from the cannula, the right ventricle was removed and the left ventricle was cut into small pieces, and dispersion of myocytes was performed by gentle agitation of tissue through a serologic pipette. The suspension was forced through a 450-µm nylon screen filtration cloth. The myocytes were then resuspended in HEPES buffer, pH 7.4, rinsed twice and allowed to settle before RNA extraction. The cell dissociation procedure routinely yields 97% to 99% myocytes and less than 1% endothelial cells or unstained cells (fibroblasts), respectively.
Polymerase chain reaction (PCR) cloning and sequencing of estrogen receptor cDNA from adult cardiac myocytes.
First-strand cDNA was synthesized from 5 µg total RNA from female and male LV cardiac myocytes, and LV tissue from male and female LVH rats using estrogen receptor gene specific primers (17) and the SUPERSCRIPT Preamplification System (Gibco Life Technologies, Gaithersburg, Maryland). Samples without reverse transcriptase (RT) served as negative controls to rule out amplification of genomic DNA. The cDNAs were used for PCR (Perkin Elmer Model 9600, Branchburg, New Jersey) using taq DNA polymerase (Gibco BRL). The temperature program for the amplifications was 30 cycles of 1 min at 94°C, 1 min at 57°C and 2 min at 72°C. Polymerase chain reaction products were resolved on a 1% agarose gel and the anticipated major PCR product of 741 base pairs was excised, purified (GeneClean II, Bio 101) and cloned into TA Cloning Vector (Invitrogen, Carlsbad, California). The resulting plasmids were transformed into DH5-alpha Escherichia coli (Gibco BRL), and recombinant DNA was purified and subjected to bidirectional automated sequencing (Applied Biosystems, Branchburg, New Jersey) at the Molecular Core Facility at Beth Israel Deaconess Medical Center.
Statistical analysis.
All values are expressed as mean ± SEM. Data in Table 1 were analyzed by two-factor analysis of variance. Otherwise, statistical significance was tested between groups using Student t test (Fig. 1) or analysis of variance for repeated measures (Fig. 2) and Fisher protected least significant difference method for post hoc analyses. Significance was accepted at the level of p < 0.05. Correlation coefficients were obtained using linear regression (the method of least squares).
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Figure 1 Left ventricular (LV) weight to tibial length ratio (left, LV/TL); LV weight to tibial length ratio as a percent of gender-matched control rats (middle, LV/TL, % Control), and LV meridional systolic wall stress (right, LV Systolic Stress). Values are mean ± SEM. LVH = LV hypertrophy.
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Figure 2 Relation between left ventricular (LV) developed pressure per gram LV (LV DevP/g) versus perfusate calcium concentration. Values are mean ± SE. Open squares = male control; solid squares = male LV hypertrophy; open circles = female control; solid circles = female LV hypertrophy. *p = 0.001 versus all groups.
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Results
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Magnitude of LV hypertrophy and in vivo function.
Characterization of animals and measurements of in vivo LV function for all groups are shown in Table 1. Body weights were significantly lower in female rats compared with male rats. Body weight was slightly lower in the male group with LVH compared with the male control group and slightly higher in the female group with LVH compared with the female control group. Tibial length, an index of growth independent of body fat, muscle mass or fluid homeostasis, was significantly greater in male compared with female rats, but there were no significant effects of LVH on tibial length. Left ventricular weight was significantly less in female hearts compared with male hearts and LV weight was significantly increased in both LVH groups. The magnitude of the increase in LVH weight was similar in male (69%) and female (68%) groups with LVH compared with their control groups (interaction p = NS). The LV weight/body weight was significantly increased in both male and female groups with LVH, and the magnitude of the increase was similar between both groups with LVH compared with their control groups (interaction p = NS). The LV weight/tibial length was increased in both male and female rats with LVH compared with gender-matched control rats, and the magnitude of the increase was similar between both groups with LVH (interaction, p = NS). There were no significant effects of gender alone on LV end-diastolic pressure, LV systolic pressure and LV systolic stress. However, there was a significant effect of LVH on all three parameters, but there was no interaction between gender and LVH (p = NS). Figure 1 illustrates the magnitude of LVH (LV weight/tibial length) in absolute values (left) and as a percent of gender control (middle), and LV systolic wall stress in male and female LVH hearts (right). The percent increase in LV weight/tibial length, and LV systolic wall stress were both similar in male and female LVH groups. Left ventricular diastolic wall stress was increased in both male and female groups with LVH compared with gender-matched control rats (4.50 ± 0.84 vs. 1.30 ± 0.14, and 2.12 ± 0.53 vs. 0.68 ± 0.12 kdyn/cm2, respectively, both p < 0.05) and was higher in male versus female LVH (p < 0.05).
Isolated heart studies: LV contractile reserve.
In the isolated perfused hearts, coronary flow rate per gram was similar among all groups (male control rats, 16.9 ± 0.7; male LVH 15.60 ± 0.7; female control rats, 16.0 ± 0.9; female LVH 16.7 ± 1.6 ml/min per g, p = NS). Left ventricular contractile reserve was examined by the dose–response relationship between LV systolic developed pressure per gram LV and perfusate calcium concentration (three calcium concentrations examined in each heart: 0.6, 1.5 and 3.0 mmol/liter) at identical LV balloon volumes. As shown in Figure 2, the LV calcium-dependent contractile reserve was similar in female LVH and control hearts. In contrast, male LVH hearts demonstrated a significantly depressed contractile reserve compared with control hearts (p  0.001). Since myocardial perfusion rates were similar in all groups, the depressed contractile reserve observed in male LVH hearts cannot be accounted for by differing levels of myocardial perfusion. Rates of contraction, assessed by first derivative of LV pressure/LV pressure, were not depressed in either male or female LVH groups, compared with their gender-matched controls (male: 66.2 ± 0.7 vs. 61.3 ± 1.0; female 65.1 ± 2 vs. 72.2 ± 4.5 s–1, respectively, both p = NS). Rates of relaxation, assessed by negative first derivative of LV pressure/LV pressure, were not depressed in either male or female LVH groups, compared with their gender-matched controls (male: 48 ± 2.1 vs. 45.4 ± 1.6; female: 36.6 ± 1.8 vs. 42.0 ± 1.9 s–1, respectively, both p = NS).
Left ventricular gene expression.
We examined LV steady state mRNA levels for fetal genes induced by pressure overload (ANF, beta-myosin heavy chain), and that modify calcium homeostasis (SERCA-2, Na+–Ca2+ exchanger). In normal male and female rats, there were no differences in LV message levels of beta-myosin heavy chain, ANF, SERCA-2 or Na+–Ca2+ exchanger (Table 2). The message levels in the LVH groups were both analyzed as absolute densitometric values, and expressed relative to values seen in same-gender control rats. The message levels of both beta-myosin heavy chain and ANF were increased in male and female LVH groups compared with their gender-matched controls, both p < 0.05; however, the expression of both genes was higher in male compared with female LVH rats (p < 0.01), as illustrated in Figure 3. A significant inverse correlation between LV developed pressure/g versus beta-myosin heavy chain mRNA levels was observed in hearts with LVH (r = 0.73, p = 0.001). As illustrated in Figure 4, the steady state SERCA-2 mRNA levels in male LVH hearts were 58% of levels in male control hearts, whereas there was only a slight and nonsignificant depression of SERCA-2 mRNA levels in female LVH hearts compared with female control hearts. Message levels of SERCA-2 normalized to the values of gender-matched control hearts were also significantly lower in male LVH hearts compared with female LVH hearts (p < 0.01). As shown in Figure 5, Na+–Ca2+ exchanger mRNA levels were significantly increased approximately twofold in both male and female LVH hearts compared with their gender-matched control groups.
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Figure 3 Beta-myosin heavy chain (top left, ß-MHC) and atrial natriuretic factor (top right, ANF) messenger ribonucleic acid (mRNA) levels normalized to glyceraldehyde phosphate dehydrogenase (GAPDH) in densitometry units, and expressed as relative increase to gender-matched control (Con) hearts. Values are mean ± SE. Bottom shows representative samples from Northern blotting showing mRNA expression of beta-myosin heavy chain, ANF and GAPDH. LVH = left ventricular hypertrophy.
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Figure 4 Sarcoplasmic reticulum Ca2+–adenosine triphosphatase (SERCA-2) mRNA levels normalized to GAPDH in densitometry units, and expressed as relative increase to gender-matched control hearts. Values are mean ± SE. Bottom shows representative samples from Northern blotting showing RNA expression of SERCA-2 and GAPDH. Abbreviations as in Figure 3.
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Figure 5 Na+–Ca2+ exchanger RNA levels normalized to GAPDH in densitometry units (left) and expressed as relative increase to gender-matched controls (right). Values are mean ± SE. Bottom shows representative samples from Northern blotting showing RNA expression of Na+–Ca2+ exchanger and GAPDH. Abbreviations as in Figure 3.
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Estrogen receptor transcript in adult LV myocytes and LV tissue.
Our findings of gender differences in gene expression in response to pressure overload raise the possibility that estrogen signaling through the myocyte estrogen receptor may contribute to these differences. To date, there are no reports of the expression of the estrogen receptor in adult cardiac myocytes, although the presence of estrogen receptor protein in neonatal cardiac myocytes and fibroblasts was recently reported (18). To determine if estrogen receptor transcript could be detected in adult LV myocytes and LV tissue, nonquantitative RT-PCR was performed on RNA isolated from female and male myocytes, and from LV tissue from female and male LVH hearts. We amplified a 741-bp cDNA fragment within two highly conserved regions of the rat uterine estrogen receptor: the DNA binding domain and the estrogen binding domain. This is shown in Figure 6. The 741-bp product was found in all samples examined and is 91% homologous to the rat uterine estrogen receptor (GenBank accession number Y00102). Also shown in Figure 6, additional smaller bands were obtained in all samples, which may represent exon skipping isoforms that have been previously described (17,19). No PCR products were obtained in samples without RT (lanes 2, 4, 6, 8).
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Figure 6 Identification of estrogen receptor transcript by reverse transcriptase polymerase chain reaction (RT-PCR). Figure shows RT-PCR products in adult rat female and male myocytes, and in left ventricular (LV) tissue from female and male LV hypertrophy (LVH) hearts. The sequence of the major 741-bp product was homologous to uterine estrogen receptor. No PCR products were obtained from negative control samples in the absence of reverse transcriptase (lanes 2, 4, 6, 8).
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Discussion
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Gender and LV hypertrophy.
Gender-related differences in the response to pressure overload have been shown in humans with aortic stenosis and hypertension (1–7). Men with aortic stenosis exhibit ventricular dilation and earlier ventricular dysfunction, which has been attributed in part to more favorable geometric remodeling in women (2). In this rat model of ascending aortic stenosis, we have also observed an earlier transition to failure manifest as LV dilation and depressed systolic performance in male compared with female subjects (11). Comparison of gender effects on LVH in humans with aortic stenosis or hypertension and young rats with ascending aortic constriction must be done with caution because clinical studies have been performed predominantly in older patients in whom confounding effects of senescence may modify cardiac growth (20).
However, recent observations in different species and models of hypertrophy suggest gender-related differences in adaptation and secondary failure. Differences in geometric remodeling and an earlier onset of impaired systolic pump performance in male versus female animals have also been reported in the spontaneously hypertensive rat model (21) and in preliminary studies of hypertrophied transgenic mice with cardiac specific expression of mutant myosin heavy chain (22). These studies have not clarified whether gender-related differences are solely related to differences in geometric remodeling or may in part be related to differences in cardiac gene expression that precede the development of heart failure. In the present study, we prove for the first time that there are striking gender-related differences in the expression of key genes that are known to play critical roles in cardiac calcium regulation and contractile function at an early stage of chronic pressure overload before the development of overt failure.
Pressure overload LVH model.
The ascending aortic stenosis rat model is a relatively pure mechanical pressure overload model in which concentric LVH with minimal collagen deposition develops in response to a sustained elevation of LV systolic pressure in the absence of systemic hypertension, or systemic neurohumoral and renin–angiotensin system activation (8–12). We chose to examine possible gender-related differences in cardiac gene expression at an early stage of compensatory LVH six weeks after aortic stenosis when cardiac dilation is absent and basal indexes of in vivo and isolated myocyte contractile function are preserved, before the later development of overt heart failure and impaired survival in male aortic stenosis rats (8–14).
In this study, the age of onset and duration of experimental aortic stenosis were identical in male and female animals, and potential variables that limit clinical studies such as duration and magnitude of aortic stenosis, coronary artery disease and the confounding variable of senescence were absent. A potential limiting factor in this model is the comparability of the imposed systolic pressure load, because a similar size clip was placed on the aortas of the male and female weanling rats, whereas the males grow to larger absolute body and heart size. For this reason, we assessed systolic load by the estimation of meridional systolic wall stress, which takes into account the magnitude of LV systolic pressure, cavity size and wall thickness. In corroboration of prior studies of female and male aortic stenosis rats at this stage of LVH (11), the magnitude of systolic wall stress was similar in male and female aortic stenosis rats. In response to this systolic pressure overload, the magnitude of LVH was similar in male and female aortic stenosis rats.
We have previously shown that calcium-dependent contractile reserve may be abnormal in isolated perfused hearts and myocytes from male rats with aortic stenosis (8,10) and rats with postinfarction remodeling (16) compared with control animals despite similar basal LV systolic contractile function indexes. We used isolated perfused hearts and observed that LV systolic pressure generation to the elevation of perfusate calcium was similar in female LVH and control hearts; in contrast, calcium-dependent contractile reserve was depressed in the male LVH hearts.
Gender and cardiac gene expression.
Interpretation of gender-related changes in cardiac gene reprogramming must take into consideration any basal differences in gene expression in normal male and female animals of identical age. There were no differences in densitometric measurements of message levels of ANF and beta-myosin heavy chain in normal male and female rats, which are present in very low abundance in the normal adult left ventricle. There were also no differences in LV SERCA-2 and Na+–Ca2+ exchanger mRNA levels in normal male and female rats. A limitation of this analysis is that we measured steady state mRNA levels and did not analyze protein levels or downstream functional events unique to these proteins. However, multiple prior studies in experimental models have shown a very close correlation between cardiac mRNA levels of these specific well-studied genes and their resultant proteins (23–33).
Pressure overload LVH in multiple animal models and human heart failure is associated with the up-regulation of cardiac genes and isoforms that are normally expressed in fetal life and down-regulated in the postnatal left ventricle (22–33). We have also detected these changes in cardiac gene expression in male rats subjected to this aortic stenosis model (12). In the present study, we made the unexpected observation that message levels of both beta-myosin heavy chain and atrial natriuretic factor were higher in male compared with female aortic stenosis animals, despite a similar magnitude of LVH as well as systolic load. Although the increase in message levels of the Na+–Ca2+ exchanger was similar in male and female LVH groups, message levels of SERCA-2 were markedly depressed in male but not in female LVH animals at this early stage of hypertrophy. These observations suggest that the "gain" of mechanotransduction of systolic load may be higher in male compared with female hearts. Alternatively, there is the formal possibility that factors such as diastolic wall stress, which was slightly higher in male versus female aortic stenosis rats, background gender-specific genetic factors or differences in hormonal growth peptides may modulate cardiac gene expression distinct from changes in LV mass.
The depression of contractile reserve that we observed in male animals with LVH compared with female rats with LVH may be explained in part by the greater up-regulation of beta-myosin heavy chain in the male rats with LVH. This up-regulation of beta-myosin heavy chain isoform is usually accompanied by variable reductions in the expression of alpha-myosin heavy chain isoform, which was not measured in this study. We observed an inverse relationship between message levels of beta-myosin heavy chain and systolic developed pressure in the male and female rats with LVH. It is well established that a reduction in myosin adenosine triphosphatase activity associated with the switch from V1 to V3 isoenzyme contributes to a slowed velocity of muscle shortening and force development in isolated muscle, which may contribute to impaired levels of force development at high work loads and physiologic heart rates (34,35). In this study, the depressed expression of SERCA-2, which was observed in the male but not the female rats with LVH, may also contribute to the depressed contractile reserve in the male group. Our observation of a potential gender-related modulation of SERCA-2 expression in pressure overload hypertrophy is novel.
The expression of SERCA-2 and its relationship to excitation–contraction coupling has been the subject of intense interest in humans and experimental models of LVH and heart failure (24–26,30–33,36–39). In the end-stage dilated failing human heart (36–38) as well as experimental models of advanced heart failure (39), message and protein levels of SERCA-2 are usually markedly depressed and associated with depressed levels of peak systolic intracellular [Ca2+]. Recent studies in end-stage failing human hearts have also shown variable increases in message and protein levels of the Na+–Ca2+ exchanger, leading to the speculation that increased activity of the exchanger in the forward mode to promote calcium efflux may modify calcium loading (40,41). In the normal rat, the contribution of Na+–Ca2+ exchange to intracellular calcium homeostasis has been shown to be much less than in other species, with a greater contribution of the sarcoplasmic reticulum adenosine triphosphatase pump (33).
Estrogen and cardiac gene expression.
In this study, we positively identified the estrogen receptor transcript in both adult male and female myocytes and LV tissue. Much further work will need to be done to determine if there are quantitative differences in message and receptor levels and their ligand-binding kinetics between male and female adult hearts. However, our observations provide proof-of-concept of the potential for estrogen to modify adult cardiac myocyte gene expression in both male and female subjects. Serum levels of estrogen are 8- to 12-fold higher in female compared with male rats (42,43). Indirect evidence strongly implicates estrogen regulation of expression of the myosin heavy chain isoforms and some other major structural proteins (42,44,45). Gender-related differences in cardiac gene expression of myosin heavy chain isoforms and structural matrix proteins were found in normal postpubertal but not neonatal rats (46), and in the spontaneously hypertensive rat (47). Future experiments are needed to elucidate the direct effects of estrogen receptor signaling on the transcription of beta-myosin heavy chain isoform, SERCA-2 and other proteins with key regulatory effects on excitation–contraction coupling.
In summary, chronic pressure overload in rats with ascending aortic stenosis is associated with gender-related differences in key cardiac genes implicated in contractile function and calcium homeostasis. Our findings support the hypothesis that gender-related differences in cardiac gene expression occur at an early stage of hypertrophy before the development of overt failure, and may contribute to the depression of contractile reserve. Future studies are warranted to determine if estrogen directly affects growth of adult myocytes and modifies transcription of cardiac genes involved in hypertrophic growth and contractility.
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Acknowledgments
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We acknowledge the important contributions of Soeun Ngoy, who contributed to the surgical preparation of the study animals. We appreciate the assistance of the Biometrics and Statistics Core Facility at Beth Israel Deaconess Medical Center.
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Footnotes
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This study was supported in part by NHLBI Grant HL5286401 (Dr. Weinberg, Dr. Douglas and Dr. Lorell). Dr. Weinberg is a 1998–1999 Biomedical Research Scholar at The Bunting Institute of Radcliffe College.
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April 1, 2000;
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28 - 49.
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K. Haghighi, A. G. Schmidt, B. D. Hoit, A. G. Brittsan, A. Yatani, J. W. Lester, J. Zhai, Y. Kimura, G. W. Dorn II, D. H. MacLennan, et al.
Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure
J. Biol. Chem.,
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D. Camper-Kirby, S. Welch, A. Walker, I. Shiraishi, K. D. R. Setchell, E. Schaefer, J. Kajstura, P. Anversa, and M. A. Sussman
Myocardial Akt Activation and Gender : Increased Nuclear Activity in Females Versus Males
Circ. Res.,
May 25, 2001;
88(10):
1020 - 1027.
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B. D. Rosen, T. Edvardsen, S. Lai, E. Castillo, L. Pan, M. Jerosch-Herold, S. Sinha, R. Kronmal, D. Arnett, J. R. Crouse III, et al.
Left Ventricular Concentric Remodeling Is Associated With Decreased Global and Regional Systolic Function: The Multi-Ethnic Study of Atherosclerosis
Circulation,
August 16, 2005;
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984 - 991.
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