Cardiovascular Research

Cardiovascular Research 1999 41(3):524-531; doi:10.1016/S0008-6363(98)00324-1
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

Estrogen, natriuretic peptides and the renin–angiotensin system¹

Mercedes L Kuroski de Bold^*

Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa ON K1Y 4W7, Canada

^* Corresponding author. Tel.: +613-761-4269; fax: +613-761-1597; e-mail: mercedes@uottawa.ca

Received 16 June 1998; accepted 15 October 1998

	Abstract

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
There are significant gender-specific differences in the incidence of hypertension and the clinical outcome of cardiovascular disease between premenopausal women and age-matched men, suggesting that sex hormones such as estrogen (E) might be responsible for the observed cardioprotective effects. This cardioprotective action of E is thought to involve lipoproteins. However, the effect of E on the lipid profile accounts for about 50% of the reduction in cardiovascular disease, indicating that there might be other mechanisms by which E exerts its cardioprotective effects. At present, the underlying mechanism of E action is poorly understood. In this review, the interplay between E, the natriuretic peptides (NP) and the renin–angiotensin system (RAS) is examined. It is hypothesized that E might, through endocrine and/or paracrine action, modulate cardiac NP in females by affecting the RAS either directly or indirectly.

KEYWORDS Hormones; Hypertension; Natriuretic peptide; Renin–angiotensin system

	1 Introduction

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
The incidence of hypertension and cardiovascular disease is significantly lower in women in their child-bearing years than in men, while after menopause, this difference disappears [1–3].

Cardiovascular mortality in postmenopausal women receiving estrogen replacement therapy (ERT) substitution is about 30–50% lower than in their untreated counterparts [4]. From this perspective, it appears that estrogen (E) might play an important role in the prevention of heart disease by lowering low-density lipoprotein cholesterol (LDL), increasing plasma levels of high-density lipoprotein cholesterol (HDL), renin substrate, promoting coronary vasodilation and improving glucose metabolism with decreased serum insulin levels [3, 5–7]. However, the effects of ERT on lipoprotein profiles, as reflected by multiple regression analysis [8], account for about 50% of the reduction in cardiovascular disease, indicating that there must be additional mechanisms whereby E exerts its cardioprotective action. Thus, the therapeutic application of E in heart disease is limited by the fact that the underlying mechanisms of E action are poorly understood. In the present review, the effects of E will be considered in relation to its impact on the cardiovascular system and hypertension through its interactions with the renin–angiotensin system (RAS) and the natriuretic peptides (NPs).

	2 Estrogen and the renin–angiotensin system

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
The RAS is one of the major regulators of blood pressure (BP), fluid and electrolyte homeostasis [9, 10]. Several lines of evidence suggest that the gender-specific differences in the development of hypertension and heart failure might be related to the activity of the RAS [11–13]. The primary components of RAS are: (1) angiotensinogen (Ango), a globular protein produced and secreted by the liver, which serves as a substrate for renin; (2) renin, an enzyme produced by the juxtaglomerular cell and released from the kidney into the bloodstream, which catalyses the hydrolysis of Ango to yield the decapeptide angiotensin I (Ang I); (3) Ang I is converted to angiotensin II (Ang II) by the angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase and (4) Ang II interacts with specific receptors in multiple target organs, of which two have been identified: AT1 is membrane bound and coupled to G protein, and AT2, which is not coupled to G protein, has unknown functions. In addition to circulating RAS, a tissue RAS is present in several extra-renal tissues where it may serve tissue-specific functions acting independently from plasma RAS [9, 12–15]. At present, the contribution of an activated endocrine and/or paracrine RAS to the progression of cardiovascular disease is not fully understood. There are indications that circulating RAS [9, 14, 16]might be responsible for mediating acute effects while tissue RAS [11, 12, 17]is involved in more chronic situations leading to secondary structural changes of the cardiovascular system and, therefore, contributes to the pathogenesis of hypertension as well as hypertrophy, coronary disease and atherosclerosis [14].

Ganten et al. [18]suggested that sex hormones might affect BP by increasing renin mRNA and gene expression levels from extra-renal tissues such as heart, adrenal gland, blood vessel wall and brain (Fig. 1). Experimental evidence supports the notion that ovarian hormones are involved in the activation of RAS and, hence, possibly of NP, because ovariectomized spontaneously hypertensive rats (SHR) had lower renin and lower renal and hepatic Ango mRNA [19]and that in both SHR-Stroke Prone (SHRSP) and transgenic rats TGR(mRen2)27 [20], which carry the salivary gland renin gene (Ren-2), ovariectomy reduced BP, active renin and Ang II immunoreactivity (ir). Most recently, Nikenig et al. [21]showed that there was an upregulation of AT1 receptor expression in aortic tissue and vascular smooth muscle cells in ovariectomized rats and that ERT downregulated this receptor.

View larger version (30K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Interactions between E, NP and RAS. EC, endothelial cell; V, vessel; ANF, atrial natriuretic factor; BNP, brain natriuretic peptide; ACE, angiotensin converting enzyme; Ang I, angiotensin I; Ang II, angiotensin II and AT1, angiotensin receptor subtype.

 
Gordon et al. [22]showed that E modulates, in a tissue-specific fashion, Ango gene expression in the ovariectomized Sprague Dawley (SD) rat. E treatment induced significant and rapid increases of Ango mRNA in liver (4 h), kidney (4 h) and aorta (1 h). Although no changes in Ango mRNA were observed in the cardiac atria, these levels were higher in intact female rats compared to ovariectomized rats. These results were not unexpected because Ango, which is primarily synthesized in the liver, is under positive control of E due to the presence in the 5' flanking region of the angiotensinogen gene of an estrogen response element (ERE) [23]. The renin promoter has also been shown to contain a putative ERE [9, 10]. It appears that the tissue RAS response to E depends on tissue-specific expression of genes containing either an ERE and/or AP-1 site. It should be mentioned that a cis-acting regulatory fragment of 556-bp in the atrial natriuretic factor (ANF) promoter is an AP-1-like site [24, 25]and thus might play an important role in the regulation of gene transcription in vivo.

It is of interest to contrast the differences between ovariectomy and ERT. Brosnihan et al. [26]showed that, in ovariectomized female transgenic rats, TGR (mRen2)27 [26], ERT reduced circulating ACE levels with a consequent reduction in plasma Ang II but without changes in plasma renin activity. ERT treatment of oophorectomized TGR (mRen2)27 rats for three weeks showed that circulating and tissue (kidney and aorta) ACE were significantly reduced. This transgenic rat line overexpresses the mouse Ren-2 renin gene, mainly in extra-renal tissues, leading to severe hypertension with cardiac hypertrophy and pathological alterations in the kidney. In contrast, in female postmenopausal (surgically induced) cynomologus monkeys [27], ERT interfered with the formation of the vasoactive Ang II while there was activation of renin activity and Ang I. It was proposed [27]that, in long-term ERT, E affects RAS by inhibiting ACE activity, thus preventing the generation of Ang II while increasing plasma renin and Ang I. Altogether, the experimental evidence indicates that E activates RAS by enhancing Ango synthesis, inhibiting ACE activity and augmenting tissue and plasma levels of Ango and renin [19, 27](Fig. 1).

The effects of E on RAS have been examined in postmenopausal women on ERT and the results are controversial [1, 3–5, 28–31]. Hassager et al. [32]found no correlation between BP and plasma renin in a two-year ERT placebo controlled study of 110 postmenopausal women. Plasma renin increased during oral treatment with estradiol but did not change with percutaneous administration. De Lignieres et al. [33]showed similar results in a group of 22 menopausal women. Indeed, Proudler et al. [34]showed in a small population of postmenopausal women (28 subjects) that, after six months of estrogen/progestagen ERT, there was a significant decrease in ACE activity. However, Scarabin et al. [35], using a similar experimental design, could not confirm the above results.

Females on oral combined contraceptives (OC) became hypertensive, with a few cases showing malignant hypertension with renal failure, thus, the hypertension developed in these patients was thought to be due to the activation of the RAS [36]. Females taking OC (30 or 50 µg), although showing high levels of plasma Ango due to E stimulation, had plasma renin activity and Ang II levels that were not significantly increased as a result of the short loop feedback inhibition of renin release by the elevated Ang II plasma levels [36, 37]. Thus, alteration in the feedback inhibition of renin release might be one of the causes for the development of hypertension.

From the above, it is clear that E in humans and in experimental models can affect RAS by reducing ACE activity, leading to a decrease in the conversion of Ang I to Ang II and by decreasing AT₁ receptor gene expression and density. The direct effects of the hormone on renin are still controversial [34, 36, 37].

If the hemodynamic alterations associated with E administration in ERT are due in part to changes in RAS, then the NP, which counteract the actions of RAS, are probably also involved in this paradigm, so that it may be proposed that E might, through endocrine and/or paracrine action, modulate cardiac NPs in females by affecting the RAS either directly or indirectly.

	3 Estrogen and natriuretic peptides

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
BP homeostasis is maintained in part by a balance between the vasoconstrictive/antinatriuretic actions of the RAS and the vasodilatory/natriuretic actions of NP. Plasma NP increase in response to volume expansion and pressure overload [38, 39], while the RAS is activated by decreases in renal pressure, contraction of plasma volume and decreased sodium delivery to the macula densa. The natriuretic peptide family is composed of three homologous peptides; atrial natriuretic factor (ANF), brain natriuretic peptide (BNP) and C-natriuretic peptide (CNP). ANF and BNP are produced by the heart. ANF is secreted by the atria and BNP is mainly secreted by the ventricles. CNP is found in the brain and in vascular endothelial cells [40–44]. NP antagonize the action of Ang II on vascular tone, inhibit renin and aldosterone secretion, renal tubule sodium re-absorption and vascular cell growth [41, 42, 45](Fig. 1).

There are two possible ways by which NP production can be affected by E. One way is through a direct effect of ovarian hormones on cardiac NP gene expression and release and the other is through one or more mediator mechanisms. One such mediator mechanism could be the RAS since it has been suggested that it is responsible for the sexual dimorphism of BP observed in the SHR [19, 46]and, furthermore, changes in the RAS induce reciprocal changes in NP.

Experimental studies designed to investigate the influence of sex hormones on NP gene expression and release are few and most focus on ANF rather than both ANF and BNP. Hong et al. [47]found that ovariectomy and orchiectomy decreased atrial ANF mRNA transcripts. In vivo pretreatment, for seven days, of gonadectomized Wistar male rats with testosterone (T) and Wistar female rats with E and P, increased atrial ANF gene expression [47]. The effects of gonadal hormones on BP, and on circulating and tissue stores of ANF and BNP were not investigated in this study [47]. The effects of gonadectomy on ANF plasma levels and tissue stores was reported by Hwu et al. [48]. ANF plasma levels and right atrial tissue stores increased in gonadectomized normotensive male rats. T-treated (five days) orchiectomized animals showed a decrease in plasma ANF levels, while atrial stores were not affected. It is unfortunate that no BP, ANF or BNP mRNA transcripts or BNP plasma and tissue levels were reported [48]. These reports are in contradiction since a good correlation between NP mRNA levels and peptide synthesis have been found previously [39]. At present, a comprehensive and systematic study on the effects of gonadal hormones on NP gene expression and release is not available. In vitro, T was shown to increase ANF synthesis and release from neonatal male atrial and ventricular cardiocytes [49, 50], while E and P did not affect ANF mRNA levels in neonatal atrial cardiocytes [51]. In addition, 1,25-dihydroxyvitamin D3 was shown to modulate the promoter activity of the ANF gene, while E was without effect [52]. This data, obtained using neonatal cardiocytes, can not be readily extrapolated to adult cardiocytes because, during postnatal life, the cardiocytes undergo dramatic changes in architecture, phenotype and cellular composition [39, 53, 54]. In addition, work from this laboratory [55, 56]has shown that ANF and BNP content and gene expression in the ventricles from normotensive and SHR are still elevated at two weeks of age and, as such, do not reflect the adult phenotype.

If E administration in ERT induces changes in the RAS, then ANF and BNP would be activated and, in turn, affect plasma renin activity and alter vascular compliance and plasma volume. This appears to be the case, since Clark et al. [57]showed that ANF plasma levels were two-fold higher in young women (25–35 years), regardless of the stage of the cycle, than in young men (25–43 years) while in postmenopausal women, plasma ANF levels were similar to those in age-matched men and increased with age in both sexes. ANF plasma levels were reported by van Hooft et al. [58]to be higher in men than in women, and Davidson et al. [59], using a small sample group, showed higher plasma renin activity and ANF levels in women taking a low dose of OC than in the early follicular phase from premenopausal women or those with or without ERT. The relationship between ovarian hormones and ANF plasma concentration during the menstrual cycle have been examined and conflicting results were obtained. Bisson et al. [60]reported no changes in ANF concentration in the two phases of the cycle but there were large changes in plasma renin and aldosterone levels during the luteal phase of the ovulatory cycle. Similar results were reported by Sealey et al. [61]in this phase of the cycle, but NP were not measured. Although Yeko et al. [62]reported no changes in ANF plasma levels, Jensen et al. [63]showed a significant decrease in the luteal phase in ten normal menstruating women. The role of BNP in women before and after menopause, as well as during the development of hypertension, has not yet been addressed.

Recent work from this laboratory [55, 56]showed that ANF and BNP production is not coordinated during the development of hypertension and that augmentation of BNP transcripts in both right and left atria from female and male SHR precedes the development of hypertension. At variance from mSHR, fSHR rats, at eight weeks of age, showed significantly lower BP with similar ANF plasma levels to those of age-matched males [55, 56]. BNP transcript levels were significantly increased in the ventricles from fSHR. It seems reasonable to propose that the high plasma NP levels and low BP seen in fSHR are the endogenous vasodilatory response to the activation of the vasoconstrictive RAS, brought about by the appearance of sex hormones in plasma at puberty. NP synthesis and secretion were shown to be altered in male TGR (mRen-2)27. Twelve week old TGR (mRen-2)27 animals showed significantly higher BP, heart rate, left ventricular (LV) weight, basal circulating irANF, LV irANF and mRNA levels than controls. In contrast, LV irBNP concentration in the TGR (mRen-2)27 was twice that of normotensives, but BNP synthesis in these animals was significantly attenuated [64]. Although the molecular and cellular mechanisms involved in the alteration of NP synthesis and release in this experimental model are not known, the results suggest that the demand for each NP in each heart chamber is differentially regulated.

Studies with ACE inhibitors at concentrations known to inhibit the RAS, both circulating and local, have shown that interference with the RAS affects NP gene expression and release in several models of hypertension [65–70]. Treatment of male SHR and male rats made hypertensive by aortic banding with ACE inhibitors induced downregulation of LV ANF mRNA while the right ventricle (RV) was not affected [71]. In contrast, atelenol (a β₁-blocker) plus doxazosin (an ₁-blocker) or doxazosin with manidipine (a calcium antagonist) did not downregulate LV mRNA [71].

The role of NP on tissue RAS is not so well understood. Kawaguchi et al. [72]showed in vitro, using bovine pulmonary artery endothelial cells, that ANF decreased and reduced the rate of conversion of Ang I to Ang II in a dose-dependent manner, indicating that ANF inhibited the activity of ACE in these cultured cells (Fig. 1). BNP was not examined in this model. There is scant information regarding the potential direct effects between the RAS and NP in spite of the fact that human right atrial appendages [73]and adult rat ventricular cardiocytes [74]were shown to express genes for all components of the RAS, namely renin, Ango and ACE [75, 76]. The experimental evidence for the existence of a cardiac RAS was recently reviewed by Ruzicka and Leenen [15], but knowledge of its interactions with NP and/or ovarian hormones during the development of hypertension is still fragmentary and little is known about its regulation and physiological significance.

	4 Estrogen and the vasculature

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
In vivo and in vitro, E was shown to diminish vascular tone by increasing production of vasodilators such as endothelium-derived nitric oxide (NO) and prostacyclin [1, 77](Table 1). Hayashi et al. [78]demonstrated that physiological concentrations of 17β-estradiol inhibited the stimulation of inducible nitric oxide (iNOS) from the murine macrophage cell line J774 by a receptor-mediated pathway. A nuclear run-on assay from human endothelial EA.hy 926 cells showed that 17β-estradiol increased endothelial NO synthetase (NOS III) mRNA due to an E-induced increase in NOS II gene transcription [79]. In rat and mouse aortic rings, 17β-estradiol induced vasorelaxation and was shown not to be mediated by nuclear estrogen receptors (ER) [80]. The calcium channel blocker properties of E, by which it may also provide cardiovascular protection, has been reviewed recently by Collins et al. [77](Fig. 1).

View this table: [in this window] [in a new window]   Table 1 Summary of the known effects of estrogen

 
The anti-mitogenic activity of E was studied in ten-week-old gonadectomized and intact male and female Sprague Dawley (SD) rats subjected to vascular injury [81]. The degree of myointimal thickening was assessed by morphometric analysis. E-treated gonadectomized animals showed a significantly decreased myointimal proliferation after balloon injury from both sexes and, in the intact female, neointimal thickening was significantly lower than that of gonadectomized rats. In contrast, myointimal proliferation in male rats was not affected by gonadectomy nor gonadectomy plus T after balloon injury and the degree of smooth muscle cell (SMC) proliferation was greater in intact males than in age-matched intact female SD rats. E, its metabolites and P have recently been shown to inhibit cardiac fibroblast (CF) growth in both male and female SD rats.

The inhibition of SMC proliferation after balloon injury and CF growth (induced by fetal calf serum) by 17β-estradiol provides evidence of the far-reaching implications of ovarian hormones in the prevention and treatment of vascular disease in humans.

	5 Estrogen, testosterone and the development of hypertension

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
Sex-hormones are known to influence cardiac mass, function and biochemistry (Table 2). Gender differences in the development of high BP has been observed in several forms of hypertension in both humans and animals. In laboratory animals, it has been shown that gonadectomy at an early age, before the rise in BP occurs, retards the development of hypertension in male and female SHR [18, 82–88]. T administration to gonadectomized rats of both sexes conferred a male pattern of blood pressure development [18, 19, 88, 89], induced significant biochemical abnormalities that could be reversed by T in males and T and E in females [88, 89]and increased body weight and heart weight in females but not in males [90]. Gonadectomy ameliorates the development of DOCA-salt hypertension in male SD rats and exacerbates its development in ovariectomized female SD rats [87], Dahl salt-sensitive and SHR rats [18, 91]. Although several mechanisms have been advanced and tested, the results were contradictory [46], except for those involving steroid hormones and the RAS.

View this table: [in this window] [in a new window]   Table 2 Sex-related differences in cardiac function and biochemistry

 
E could also exert cardiovascular protection in females by a direct effect upon the heart through a hormone receptor-mediated mechanism(s) [92, 93].

	6 Estrogen and estrogen receptors in the heart

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
E modulates gene transcription by direct genomic effects (involving de novo synthesis of protein) after binding to ERE in the promoter region of estrogen-responsive genes, or by stimulation of transcription from promoters containing an AP-1 site. The details of the mechanism of action of the latter is not known. ER have been detected by autoradiography [94]and by ligand binding of radiolabelled 17β-estradiol in the cardiovascular system of several species [93, 95, 96]. In male and female baboons, a sexually dimorphic pattern in the myocardial cellular distribution of the androgen receptor (AR) but not in the ER and progesterone receptor (PR) was shown [96]. Androgen receptors in female baboon myocardium was localized in the cytosol, while in male baboon myocardium, the receptors were found in both the nucleus and the cytosol. E stimulates fibroblast growth in neonatal rat cardiocytes and significantly induces the immediate early gene product c-Fos [92]. Recent studies indicate that these ER are functional. The E precursors androstenedione and T were shown to stimulate the expression of ER and -β in neonatal rat cardiocytes in a gender-specific fashion [97]. Transfected neonatal cardiocytes with ERE–LUC plasmid (containing three copies of the vitellogenin ERE) after incubation with E precursors showed that induction of the reporter plasmid was higher with androstendione than T, suggesting that the former is metabolized to E to a higher degree than is T. Furthermore, a sexual dimorphic pattern was found for ER only higher expression was seen in female cardiocytes compared to males using the same incubation conditions [97]. In contrast, ERβ was not influenced by gender.

	7 Conclusion

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 
Gender-specific differences are observed in humans and animals during the development of hypertension [56, 98–102]. It is evident that sex significantly affects NP gene expression and production during the development of hypertension but no data is available to indicate whether these are the result of direct or indirect effects of ovarian hormones. Since E stimulates the RAS and the vasoconstrictive/antinatriuretic actions of RAS are counterbalanced by the vasodilatory/natriuretic effects of NP, it is feasible that E, through the RAS, might exert short and/or long term effects on the endocrine heart. Elucidating these short and/or long term effects may help develop gender-based implementation of therapeutic cardiovascular strategies.

Time for primary review 30 days.

	Acknowledgements

 
Thanks to Carole Frost for editing the manuscript and to Paul G. de Bold for the art work.

	Notes

 
¹ Supported by Heart and Stroke Foundation of Ontario.

	References

Top Abstract 1 Introduction 2 Estrogen and the... 3 Estrogen and natriuretic... 4 Estrogen and the... 5 Estrogen, testosterone and... 6 Estrogen and estrogen... 7 Conclusion References

 

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