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Cardiovascular Research 2004 63(3):510-519; doi:10.1016/j.cardiores.2004.03.027
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Copyright © 2004, European Society of Cardiology

Gender modulates cardiac phenotype development in genetically modified mice

Xiao-Jun Du*

Experimental Cardiology Laboratory, Wynn Domain, Baker Heart Research Institute PO Box 6492, Commercial Road, Melbourne, Victoria 3004, Australia

* Tel.: +61-3-92762028; fax: +61-3-85321100. Email address: xiaojun.du{at}baker.edu.au

Received 4 January 2004; revised 28 March 2004; accepted 29 March 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Sex differences in...
 3. Mechanism: role of...
 4. Mechanism: molecular pathways...
 5. Implications and perspective
 References
 
Recent research using genetically modified mice has revealed significant sex differences in cardiac phenotypes. In the majority of strains, females display a lower mortality, less severe hypertrophy, better preserved function and mitigated cardiac pathology compared with male counterparts. Thus, gender is an independent determinant for the development of cardiac phenotype in murine models. While there is strong evidence for estrogen as a cardiac protector, emerging evidence indicates adverse actions of testicular hormones that might be responsible in part for the sex differences. Studies using mouse models have also revealed novel information on signalling mechanisms mediating the sex difference.

KEYWORDS Hypertrophy; Heart failure; Gender; Estrogens; Transgenic animal models


   1. Introduction
Top
 Abstract
 1. Introduction
2. Sex differences in...
 3. Mechanism: role of...
 4. Mechanism: molecular pathways...
 5. Implications and perspective
 References
 
Sex differences in cardiovascular morbidity and mortality have long been recognized. The mechanism is believed due largely to protective actions of female hormones [1], evidenced by increased cardiovascular risk in women after menopause and by cardiovascular benefits of estrogen replacement therapy when studied clinically and experimentally, although the latter has been challenged by negative outcomes from recent clinical trials [2,3].

Genetically modified mice have merged as powerful tools for cardiovascular research. Recent studies using this class of models have generated novel information on sex dimorphism in the development of cardiovascular phenotype. For instance, using strains of mice with disruption of ApoE, low-density lipoprotein receptor, estrogen receptors (ER), aromatase or follitropin receptor (both lead to estrogen deficiency), several groups have convincingly shown that estrogen and ER-mediated signalling are protective against vascular dysfunction and atherosclerotic lesions [4–8]. This review will focus on recent findings from genetically modified mice on sex differences in cardiac phenotype development and the mechanisms involved.


   2. Sex differences in cardiac phenotype development
Top
 Abstract
 1. Introduction
 2. Sex differences in...
3. Mechanism: role of...
 4. Mechanism: molecular pathways...
 5. Implications and perspective
 References
 
Studies on a number of mouse strains have observed multiple differences between male and female animals, including male-gender-dependent phenotype development, degree of hypertrophy, severity of cardiomyopathy and dysfunction, survival, and consequences following an ischemia/reperfusion insult.

2.1. Male gender-restricted cardiac phenotype
In several strains, pathological phenotypes are detected only in male mice [9–19] (Table 1). FKBP12.6 is a sarcoplasmic reticulum (SR) membrane protein that regulates the gating of ryanodine receptor-2 (RyR2) [20]. Disruption of FKBP12.6 gene leads to increased probability and prolongation of channel opening, with subsequent increment in Ca2+-induced–Ca2+-release gain and contractile force in mouse hearts of both genders [9]. However, only male FKBP12.6 null mice developed myocardial hypertrophy [9]. Genetic manipulations may also retard cardiac growth and this phenotype has been reported in several models that exclusively or predominantly affect male animals [10–12,19]. A good example is the strain with duel knockout of {alpha}1A/B-adrenergic receptors (AR), in which developmental cardiac growth was impaired in male mice leading to a smaller heart size by 16% and reduction in myocyte size by 33% [10]. These changes, however, were not present in female mice. The significance of the phenotype seen in the male mice is indicated by an attenuated exercise capacity and a higher heart failure mortality when animals were subjected to pressure-overload [10]. Similarly, retarded cardiac development was observed only in male mice with disruption of insulin growth factor-I (IGF-I) [19] or expression of mutant troponin T [11] or myostatin [12]. Cardiomyopathy in several models was also restricted to male gender. For example, we recently observed, in male but not in female mice, fibrotic cardiomyopathy resulted by disruption of relaxin-1, an anti-fibrotic hormone [13]. In a transgenic (TG) strain with cardiac-restricted overexpression of β1AR, only male mice were used in subsequent studies [14,15,21] because, unlike males, female mice do not have a cardiomyopathy phenotype (Engelhardt, personal communication).


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  		Table 1 Cardiac pathological phenotypes that developed in male but not in female mice

 
2.2. Myocardial hypertrophy
Existing data suggest that male mice are more sensitive than their female counterparts to genetic interventions leading to pathological hypertrophy. For instance, a 4-fold overexpression of phospholamban resulted in left ventricular (LV) hypertrophy which became evident in TG males at 15 months of age whilst no hypertrophy was observed in females [22,23]. Myocardial hypertrophy due to β2AR overexpression was also more prominent in male than in female mice during 9 to15 months of age [24]. A further example is guanylyl cyclase-A (GC-A, or natriuretic peptide receptor-1, Npr1) knockout strain, in which hypertrophy and enhanced expression of hypertrophy-associated genes were more pronounced in males than females at 3 months of age [25].

2.3. Ventricular dysfunction and heart failure
Sex differences in the onset and progression of myocardial dysfunction and heart failure have been reported in murine models with females usually showing a better preservation of function than males [13,23,24,26–32]. These findings are in keeping with the observations from other species, including human, that males in general have an earlier transition into heart failure than female counterparts [33–35].

Expression of mutant (R403Q) {alpha}-myosin heavy chain ({alpha}MHC) leads to an early onset of hypertrophic cardiomyopathy and LV diastolic dysfunction but with a normal or supranormal systolic function [26,27]. Mice of both genders developed hypertrophy to a similar degree at 3 months of age. By 9 months of age, however, the female mice continued to exhibit concentric hypertrophy whereas the male mice began to show signs of LV dilatation, systolic dysfunction and exercise intolerance [27–29]. Moreover, TG males had a higher incidence than females of left atrial thrombus, a sign of heart failure [26].

Overexpression of β2AR by 200-fold leads to an age-dependent cardiomyopathy [36]. In this model, male and female TG mice differ in almost every pathophysiological component of cardiomyopathy with significant female-advantage over male [24]. While both genders showed a progressive decline in contractile function with ageing, male mice usually degenerated into dilated cardiomyopathy with high incidence of heart failure death whereas female mice exhibited only moderate LV dysfunction [24].

Cardiac-restricted expression of tumour necrosis factor {alpha} (TNF{alpha}) leads to severe cardiomyopathy [30]. Studies on this model have shown that male mice exhibited more marked LV wall thinning, dilatation and dysfunction together with blunted functional responses to β-agonist stimulation, indicating dilated cardiomyopathy. Whilst female mice showed increase in LV wall thickness without changes in chamber dimension, and maintained responses to isoproterenol stimulation [30]. In mice overexpressing either wildtype (4-fold) or mutant (V49G, 2-fold) phospholamban, male mice had an earlier transition from concentric hypertrophy to LV failure compared with female counterparts [23,32]. More specifically, LV chamber dilatation due to overexpression of wildtype phospholamban was noticed in male TG mice between 6 and 15 months of age, but not seen in females until 22 months of age. Furthermore, expression of mutant phospholamban leads to LV contractile dysfunction in young males but not in females [32].

On the other hand, an association of the female gender with increased susceptibility of myocardial dysfunction was described in a few models [37,38]. For example, in mice with cardiac-restricted overexpression of platelet-derived growth factor-C (PDGF-C), although both genders similarly developed hypertrophy, only female animals showed dilated cardiomyopathy, heart failure and sudden death [37]. In another model with cardiac overexpression of alcohol dehydrogenase, inhibition by ethanol of myocyte contraction was much more pronounced in female than that in male mice, likely due to different sensitivity to a higher content of acetaldehyde, an oxidized product of ethanol via alcohol dehydrogenase [38].

2.4. Survival in strains with cardiomyopathy
Premature death due to cardiomyopathy occurs in numerous models and sex-related survival difference has been observed in several strains [23,30–32,37,39,40,42]. In these strains, females usually have a survival-advantage over males with a delayed onset of death and a better survival during the study period (Table 2). Moreover, sudden cardiac death was reported only in male mice with cardiac-restricted expression of mutant {alpha}MHC or GC-A knockout [25,43]. The male {alpha}MHC TG mice had a longer QT interval than females and die suddenly during stress, such as exercise [43].


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  		Table 2 Sex difference in the survival of mouse strains with cardiomyopathy phenotypes

 
2.5. Severity of ischemia/reperfusion injury
Under conditions of cardiac ischemia/reperfusion, sex differences have been reported in several mouse strains with regard to LV dysfunction, ATP depletion, intracellular accumulation of Na+ and Ca2+ and degree of acidosis [16,17,44–46].

In Langendorff-perfused hearts from mice overexpressing β2AR or Na+/Ca2+ exchanger (NCX) [17,44], ischemia-induced fall in intracellular ATP content and pH was more profound in hearts of TG male than wildtype male mice [16,17,45]. During subsequent reperfusion, recovery in LV function and ATP content was also poorer in TG than wildtype hearts of male animals, indicating a more profound ischemia/reperfusion injury in TG males. In contrast, no difference was observed in these parameters between TG and wildtype female groups [16,17,44]. In cultured cardiomyocytes from NCX TG mice, increment in intracellular Na+ and Ca2+ following metabolic inhibition to simulate ischemia was substantially greater in TG male than that in both wildtype male and TG female groups [44], implying energy depletion-mediated Ca2+ overload as a responsible factor for the sex difference in ischemia/reperfusion injury. Cross et al. [46] reported that disruption of phospholamban markedly sensitised the heart to ischemia/reperfusion injury which was similar for both genders. Following a brief ischemia (15 min), however, recovery in LV function and tissue content of ATP was significantly better in hearts of females than male phospholamban null mice [46]. Considering that sex differences in ischemia/reperfusion injury in the β2AR TG strain are similar to that seen in the NCX overexpression or phospholamban knockout strains, it is likely that Ca2+ overload is a key factor mediating these differences in the β2AR TG model.

Role of ER in myocardial ischemia/reperfusion injury has also been investigated using ER{alpha} null mice [45]. Compared with the wildtype male group, perfused hearts from ER{alpha} knockout mice displayed more severe dysfunction, higher incidence of arrhythmias, and a 5-fold greater Ca2+ accumulation during ischemia/reperfusion [45]. Furthermore, nitric oxide production and coronary flow during reperfusion were also significantly lower in knockout than in wildtype mouse hearts.

2.6. Cardiac pathology and healing
Important sex differences exist in the degree of cardiac pathology in a variety of mouse models [13,24–26,30,37,39,47]. By quantitative histology, we observed, in the β2AR TG strain, that collagen content and the number of apoptotic myocytes were greater in male than female hearts [24]. Similarly, more severe myocyte death and fibrosis were observed in hearts of male mice of TG (TNF{alpha}, {alpha}MHC mutant, PDGF-C) or knockout (GC-A, relaxin) strains [13,25,26,30,37,39,47]. In GC-A knockout strain, male mice also had higher expression levels of transforming growth factor β (TGFβ1, TGFβ3) and pro-collagens, together with a higher collagen content than in female hearts (4-fold versus 40%) [39].

Sex dimorphism in the healing process has also been reported in MRL mouse strain which is unique in its healing properties [48,49]. The MRL mice are able to heal cryogenically induced massive injury to the heart within 60 days with a full restoration of cardiac structure and function by regeneration rather than scarring process [48]. Further studies indicate that, following experimental injury, female MRL mice heal much quicker and more complete than their male counterparts [49]. Studies are in progress to investigate if sex difference in the healing procedure also exists in the heart of the MRL mice (Heber-Katz, personal communication).

Collectively, genetically induced cardiomyopathy preferentially affects the male gender in a majority of mouse models and female animals, when affected, have a lower mortality and less severe dysfunction and pathology than male mice. These findings are in keeping with studies on human or other laboratory species. Sex difference in survival is unique to this class of models and will be very useful for future research. In all TG models, the sex dimorphisms are not due to gender difference in the level of transgene expression.


   3. Mechanism: role of gonadal hormones
Top
 Abstract
 1. Introduction
 2. Sex differences in...
 3. Mechanism: role of...
4. Mechanism: molecular pathways...
 5. Implications and perspective
 References
 
The precise mechanism underlying sex differences in cardiovascular risk is not fully understood. Results from in vitro and in vivo studies have indicated that sex steroids, particularly estrogen, play a pivotal role [1]. To address the role of gonadal hormones in the sex difference of murine models, two approaches have been adopted: pharmacological intervention and depletion of sex hormone by gonadectomy.

3.1. Effects of ovarian hormones
Four studies have addressed the influence of ovariectomy on sex differences in the cardiac phenotype using knockout ({alpha}1A/BAR, GC-A) or TG (β2AR, NCX) strains [10,17,24,39], and three studies showed a lack of influence by ovariectomy [10,24,39]. Unlike male {alpha}1A/BAR double knockout mice which showed retarded cardiac growth and reduced exercise tolerance, intact or ovariectomised female mice did not have this phenotype [10]. Similarly, in the cardiomyopathy strain due to β2AR overexpression, ovariectomy had no effect on the gender differences in survival, ventricular dysfunction and myocardial histopathology [24]. Furthermore, in the GC-A knockout strain, ovariectomy also exerted no effect on the sex difference in the degree of cardiac hypertrophy and fibrosis [39]. The only study that showed an effect by ovariectomy was by Cross et al. [17] who observed, in perfused hearts from NCX TG mice, that overiectomy blunted functional recovery following ischemia/reperfusion compared with intact females, indicating a protective role of estrogen. Despite of this effect, the degree of functional recovery was still better in ovariectomised female than in male NCX TG hearts [17].

Numerous studies have shown that female-related phenotype can be mimicked by the use of estradiol in males or in ovariectomised females, or blocked with ER antagonists. For example, estradiol treatment markedly improved survival of male mice disrupted of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) [18], or prevented catecholamine-mediated activation of p38 mitogen-activated protein kinase (p38-MAPK) in cardiomyocytes of phospholamban TG mice [23]. In cardiomyocytes prepared from male NCX TG mice, acute exposure to estradiol dose-dependently attenuated energy depletion-mediated rise in intracellular Ca2+ concentration and abolished the sex difference in the extent of Ca2+ overload [44]. Moreover, in the FKBP12.6 knockout female mice, blockade of ER with tamoxifen induced LV hypertrophy to a level similar to that seen in male animals thereby abolished the sex difference in hypertrophy-development [9]. In keeping with this finding, treatment with estradiol in the ovariectomised female mice reduced pressure-overload hypertrophy and activation of p38-MAPK [50].

3.2. Effects of testicular hormones
While the role of estradiol and ER has received great interest, potential influence by androgens has been much less studied. Interestingly, recent findings have suggested a deleterious role of androgens in the development of pathological phenotype in the heart [10,24,39,49]. Following orchidectomy in the β2AR TG and wildtype males at 12 weeks of age, we observed, during the subsequent 12-month follow-up period, alleviation of the cardiomyopathy phenotype, including reduced degree of hypertrophy, improved survival and significant reversal in LV dysfunction and remodeling [24]. Similarly, in the MRL mice with an unusual healing capacity which was superior in females than males, orchidectomy improved healing whereas ovariectomy showed no effect [49]. Li et al. [39] reported, in GC-A knockout mice, that whilst ovariectomy exerted little effect on the sex difference in hypertrophic and fibrotic phenotypes, orchidectomy at 10 weeks of age or the use of the androgen receptor antagonist flutamide significantly attenuated the extent of myocardial hypertrophy and fibrosis. Interestingly, they observed that sex differences in hypertrophy and fibrosis were abolished by simultaneous disruption, through cross-breeding, of AT1a receptor in the GC-A null males [39] and that a sub-pressor dose of angiotensin II exacerbated the cardiac hypertrophy and augmented interstitial fibrosis in GC-A knockout but not in wildtype animals [51]. Thus, these findings raise the possibility that AT1a is involved in signalling of androgen-mediated sex differences.

Caution should be taken when interpreting findings from testosterone treatment. Nathan et al. [52] have shown, in orchidectomized LDL-receptor deficient mice, that treatment with testosterone or estradiol similarly reduced the extent of atherosclerotic lesion in the aorta. They further showed that aromatase was expressed in the aorta and that the beneficial action of testosterone was abolished by concomitant inhibition of aromatase using anastrazole, indicating that testosterone is converted into estradiol, which in turn exerts its vascular protection [52]. Whether this is also applicable to the heart remains to be investigated.


   4. Mechanism: molecular pathways mediating the sex differences
Top
 Abstract
 1. Introduction
 2. Sex differences in...
 3. Mechanism: role of...
 4. Mechanism: molecular pathways...
5. Implications and perspective
 References
 
While recent data collected from mouse models are in keeping with our existing knowledge, novel information has been generated regarding signalling mechanisms that mediate sex dimorphism in the mouse heart.

4.1. Ion channels, exchangers and regulators
Na+ and Ca2+ transients across the plasma membrane and SR are under delicate regulation by factors including ion channels, exchangers, and SR regulatory proteins [20]. The involvement of these factors in sex dimorphism in phenotype development is indicated by the fact that significant sex differences exist in a number of models with gene manipulation targeting these factors (Table 3) [9,14–17,21,22,30,32,35,40,44,46,53,54].


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  		Table 3 Sex differences in cardiac phenotypes of mice with genetic modification targeting ion exchangers, channels and regulators

 
Cardiac overexpression of β1AR dramatically upregulated Na+/H+ exchanger-1 (NHE1) [15]. Importance of NHE1 in cardiomyopathy-development in this model is indicated by the fact that treatment with the NHE inhibitor cariporide abolished premature death, cardiac hypertrophy, fibrosis and dysfunction in males [15]. Further, Engelhardt et al. [21] reported in male TG hearts an increased expression of junctin, a transmembrane protein that regulates the interactions between RyR and SR Ca2+-binding protein calsequestrin [21]. Whether gender differs in cardiac levels of NHE1 and junctin in this TG strain warrants further investigation.

Increased expression of L-type Ca2+ channel was observed in cardiomyocytes from ER knockout mice [54]. Estrogen is able to inhibit L-type Ca2+ currents in cardiomyocytes thereby lowering intracellular Ca2+ concentration at systole [55]. When subjected to pathological stimuli, more profound abnormalities in Ca2+ transients occur in the myocardium of knockout than wildtype male mice leading to increased intracellular Ca2+ [54]. A potential consequence of this is activation of Ca2+-dependent hypertrophic signalling pathways, like calcineurin/NFAT and MAPK with a more marked hypertrophy-development in males than females. In addition, a higher expression level of KATP channels has been demonstrated in the female than male mouse myocardium, a difference that is attributable to estrogen and mediates protection against ischemia/reperfusion [56,57].

4.2. Nitric oxide synthases (NOS)
Current data from mouse models indicates that activation of eNOS by estrogen mediates cardiovascular protection. Simoncini et al. [58] showed that ER{alpha} binds to a regulatory subunit (p85{alpha}) of PI3K, thereby activating protein kinase B (PKB) and eNOS, and that the use of inhibitors of PI3K or eNOS abolished estrogen's protection against vascular injury following ischemia/reperfusion. In perfused hearts, nitric oxide production via eNOS is higher in female than male β2AR TG mice, which is responsible for an ameliorated ischemia/reperfusion injury in the former [16]. Treatment with L-NAME to inhibit eNOS exacerbated ischemia/reperfusion injury in the perfused hearts of female mice with phospholamban disruption or with β2AR overexpression, but not in their male counterparts [16,46]. Similarly, ischemic injuries to the heart and blood vessels were more severe in the eNOS knockout than wildtype mice [59]. Further supportive evidence comes from studies showing that estradiol activates expression and activity of eNOS via stimulation of ER{alpha} [60,61] and that ER{alpha} disruption diminishes nitric oxide production by eNOS during ischemia/reperfusion in hearts of male mice [45,61].

The role of iNOS in mediating sex-related differences in the cardiovascular system remains controversial. Overexpression of iNOS in the heart of eNOS knockout mice restored in part the benefits mediated by eNOS [62]. However, inhibition of eNOS, but not iNOS, exacerbated ischemia/reperfusion injury in the heart of β2AR TG females to the degree similar to that seen in the TG males [16], indicating a protection mediated by eNOS rather than iNOS. Sex differences exist in the cardiomyopathy due to overexpression of TNF{alpha} [30], a cytokine known to induce a robust expression of iNOS [47]. In this model, acute inhibition of iNOS improved functional responses to β-adrenergic stimulation, indicating an inhibitory effect of iNOS-derived nitric oxide on myocardial contractile function [47].

4.3. Expression of angiotensin-converting enzyme (ACE), TNF receptors and TGFβ
Freshour et al. [63] reported that ACE was 1.5–2-fold more abundant at mRNA and protein levels in ventricles of male than female mice, differences that become more apparent with ageing. Sex difference in ACE expression is likely attributable to sex steroids as indicated by a 28% elevation following ovariectomy but a 37% reduction by orchidectomy [63]. We observed, in the β2AR TG mice, a 40% higher TGFβ1 expression in male but not in female hearts in comparison with respective wildtype counterparts [24]. Similarly, GC-A deficient males had higher mRNA levels of TGFβ1, TGFβ3 and pro-collagens than females, in keeping with a greater extent of myocardial fibrosis in the former [39]. Although increased TGFβ1 expression was observed in TNF{alpha} TG mice, sex difference in this phenotype was not reported [30].

Kadokami et al. [30] observed, on both TNF{alpha} TG and wildtype mice, much higher levels of expression and activity of TNF-receptors in the heart (but not in other organs) of male than female mice and this is largely responsible for the sex difference in cardiomyopathy in this model. Further investigation is required to determine whether gender differences in TNF-receptor content and activity contribute to sex dimorphism in cardiovascular disorders in general.

4.4. PKB and p38-MAPK pathways
PKB (or Akt) is a central signaling molecule in the regulation of cell survival and glucose metabolism [64,65]. After phosphorylation, PKB is activated and translocated into the nucleus where it phosphorylates substrates, including a pro-apoptotic transcription factor forkhead which then relocates into cytosol. Cardiac-restricted overexpression of IGF-I, a growth factor capable of stimulating PI3K/PKB pathways, increased the level of nuclear-localised phospho-PKB and cytosolic phospho-forkhead in hearts of TG than in wildtype mice, and these indices were over 2-fold higher in female compared with that in male TG hearts [64,66]. A higher PKB activity might be beneficial as indicated by studies showing that overexpression of IGF-I is protective against ischemia/reperfusion or infarction [67,68] or rescues tropomodulin overexpression-induced cardiomyopathy [69], and that nuclear-localised PKB expression enhances inotropy and prevents cell death [70]. Interestingly, treatment with estradiol or genistein elevated nuclear phospho-PKB localisation [66]. Sex differences in PKB and forkhead were also observed in the human myocardium. Quantity of nuclear phospho-PKB and phosphorylated forkhead is significantly higher in the myocardium of premenopausal women than age-matched men [66]. These differences may contribute to a less-frequent apoptotic myocyte death in failing hearts of women than men [68,71]. Possible mechanisms responsible for the benefits of PKB activation include PKB's actions of inhibiting caspase-9 and forkhead [72] and stimulating glucose uptake due to upregulated expression of glucose-transporter GLUT4 [73].

P38-MAPK potently induces hypertrophic gene expression and sarcomeric re-organization, thereby contributing to the transition into heart failure [74,75]. P38-MAPK is inhibited following dephosphorylation by MAPK kinase phosphotase-1, MKP-1 [65]. Indeed, myocardial hypertrophy due to higher plasma levels of catecholamines in the phospholamban TG mice was related to a suppressed MKP-1 activity with subsequent disinhibition of p38-MAPK [23]. In ovariectomised mice, aortic constriction resulted in activation of p38-MAPK and pressure-overload hypertrophy, changes that were significantly inhibited by estradiol treatment [50]. Intriguingly, estrogen appears to specifically inhibit p38-MAPK but does not alter either content or activity of c-Jun N-terminal kinase (JNK), or extracellular signal regulated kinase (ERK1/2) [50].

Myosin enhancer factor 2 (MEF2) transcription factors are critically involved in the embryonic and postnatal cardiac development and hypertrophy [65,75–77]. Leinwand's group (Leinwand, conference communication) has shown that MEF2 activity is higher in male than female mice with hypertrophic cardiomyopathy due to {alpha}MHC mutation or with exercise-induced hypertrophy.

4.5. PPAR{alpha}-regulated energy metabolism and mitochondrial biogenesis
Three PPAR, {alpha}, {gamma} and {delta}, have been identified in mammals as the nuclear receptor superfamily with each subtype showing distinct tissue distribution [78]. PPAR can be activated by a variety of fatty acids and fatty acid derivatives or analogues. Binding of PPAR{alpha} with its co-factors to promoter-responsive sites alters transcription of a large number of distinct target genes (Fig. 1) [78]. Most known PPAR{alpha} target genes encode for transporters and enzymes of the peroxisomal, mitochondrial and cytochrome P450 pathways that are involved in cellular fatty acid influx and oxidation. Thus, PPAR{alpha} is the chief regulator of fatty acid catabolism and storage [78]. Considering a high capacity of energy production through mitochondrial fatty acid β-oxidation in the myocardium under physiological conditions and dramatic changes in energy substrate utilisation under diseased conditions, PPAR{alpha} likely plays a central role in the control of myocardial energy metabolism [78]. In this regard, it is interestingly to see that three studies to date have implicated the involvement of PPAR{alpha}-regulated energy metabolism in sex differences observed in the heart [18,79,80].


Figure 1
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  		Fig. 1 Peroxisome proliferator activated receptor {alpha} (PPAR {alpha}) is a key transcriptional regulator for a range of mitochondrial transporters and enzymes that involve mitochondrial energy substrate influx and utilisation. By heterodimerzing with retinox X receptor (RXR), PPAR{alpha} binds to specific promoter DNA response elements thereby modulating gene expression. The PPAR{alpha}-activated receptor {gamma} coactivator-1, PGC-1, interacts with PPAR{alpha} and recruits other co-factors to promote target gene transcription. PGC-1 per se is also a key regulator for mitochondrial biosynthesis and function. FA denotes fatty acid.

 
While being viable under baseline conditions, PPAR{alpha} null mice have defects in lipid utilisation and glucose homeostasis [18]. When they were challenged by treatment with carnitine palmitoyltransferase-1 inhibitor to block mitochondrial fatty acid flux, male mice showed massive accumulation of intracellular lipid and depletion of glycogen store in the heart and liver, profound and sustained hypoglycemia and poor survival [18]. Interestingly, these phenotypes were not present in the majority of females [18]. Likewise, more profound disturbance in lipid metabolism occurred in the male PPAR{alpha} null mice with concomitant expression, by cross-breeding, of lipoprotein lipase (LPL) in skeletal and cardiac muscles [79]. In these mice with dual genetic manipulations, males had a very poor survival (45% at 4 months and 0% at 11 months of age) with signs of acute pulmonary congestion at autopsy. In comparison, females had 100% survival throughout 12 months, although they, like male counterparts, developed LV dysfunction likely due to lipid toxicity and/or deprivation of energy substrate utilisation [79].

Histone deacetylases (HDACs) deacetylates histones thereby inducing heterochromatin remodeling and gene repression. Frey and Olson [75] and Zhang et al. [81] have shown that phosphorylation of HDACs promotes its binding with protein 14-3-3 followed by cytosolic relocation and disinhibition of MEF2-mediated gene transcription. In adult male mice, induction of cardiac-restricted expression of a mutant signal-resistant form of HDAC5 (HDAC5S/A, which is unable to bind with 14-3-3) markedly suppressed expression of mitochondrial enzymes and PPAR-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) and all males died in the form of sudden death within 10 days [80]. In sharp contrast, all female TG mice survived at least over 30 days indicating gender-specificity in response to HDAC5S/A [80]. Histological examination revealed signs of cardiomyocyte necrosis, inflammation and gross aberrations in mitochondrial structure in hearts of males, but collagen deposition and chamber dilatation in hearts of female, suggesting gender differences in the process of pathogenesis [80].


   5. Implications and perspective
Top
 Abstract
 1. Introduction
 2. Sex differences in...
 3. Mechanism: role of...
 4. Mechanism: molecular pathways...
 5. Implications and perspective
References
 
While most previous studies on sex-related cardiovascular risk have emphasised the importance of the vascular system, recent studies on a number of genetically modified mouse models have shown significant sex differences in cardiac phenotype, as summarised in this review. Clearly, not every mouse model has sex dimorphism in the cardiac phenotype. However, considering the facts that sex differences in cardiovascular morbidity and mortality develop with ageing and that a number of reports have only studied mice at a young age, it remains to be investigated if sex differences do occur in other mouse models when research extends to animals with an advanced age. Thus, studies on phenotype determination need to balance gender ratio to avoid misleading information when a sex difference does exist. In addition, the significance of some sex-related phenotype diversities warrants further investigation.

Genetic background of mice might influence the development of sex dimorphism in the murine cardiac phenotype. For example, while disruption of FKBP12.6 in 129sv strain resulted in hypertrophy in male but not female mice [9], this sex-related phenotype was not observed in FKBP12.6 null mice with DBA/C57B6 background [82].

In recent decades, research on sex-related difference in the cardiovascular system has been focused on demonstrating the role of gonadal hormones. It is widely held that sex differences in the susceptibility of cardiovascular diseases are related to estrogen status. Thus, one would expect to see beneficial effects by treatment with estrogen but deleterious consequences following ovariectomy. Interestingly, in most instances those studies that adopted estrogen treatment yielded beneficial outcomes whilst others that used ovariectomy showed no detrimental effect. The reason for such different outcomes remains unclear. The age of gonadectomy might be an important issue because some genetic programs responsible for the sex dimorphism could have been activated upon early exposure to sex steroids. However, a sharp rise in cardiovascular risk in post-menopausal women does suggest the importance of prevailing ovarian hormones. In this regard, it is useful to know that the menopausal period in female mice lasts up to 15 months of age [83]. Future research should make full use of the strains with conditional disruption of ER, androgen receptor or aromatase by cross-breeding them with other strains showing sex differences in cardiac phenotype. Moreover, diet-derived phytoestrogens as a potential source of ER ligands are worth further investigation, as indicated by Leinwand [11].

The specific molecular mechanism underlying the sex difference in cardiovascular diseases remains poorly understood. Recent studies using mice have yielded novel information on some fundamental issues such as molecular signalling, energy metabolism and post-injury repair. Further investigation using genetically modified mice is expected to improve our understanding on sex dimorphism and molecular mechanisms in cardiac physiology and pathophysiology. In addition, the sex-related survival differences in several mouse models would be useful in future research.


   Acknowledgements
 
This work was supported by grants from the NHMRC of Australia and National Heart Foundation of Australia. I am grateful to Dr Helen Kiriazis for her helpful comments.


   Notes
 
Time for primary review 28 days


   References
Top
 Abstract
 1. Introduction
 2. Sex differences in...
 3. Mechanism: role of...
 4. Mechanism: molecular pathways...
 5. Implications and perspective
 References
 

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