(Hypertension. 1999;33:323-328.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Estrogen Regulation of Angiotensin-Converting Enzyme mRNA
From The Hypertension and Vascular Disease Center, Division of Surgical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Patricia E. Gallagher, The Hypertension and Vascular Disease Center, Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1032. E-mail pgallagh{at}wfubmc.edu
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Abstract—Estrogen replacement therapy is cardioprotective in postmenopausal women; however, the precise molecular mechanisms for this modulation are not fully elucidated. We previously showed that chronic estrogen replacement therapy reduced angiotensin-converting enzyme (ACE) activity in tissue extracts and serum with an associated reduction in plasma angiotensin II. A reverse transcriptase–polymerase chain reaction assay was developed to determine whether estrogen treatment regulates tissue ACE mRNA concentration. Total RNA was isolated from kidney cortex, kidney medulla, lung, and aorta of ovariectomized Sprague-Dawley rats after 21 days of chronic 17ß-estradiol replacement therapy (5 mg pellet per rat SC) or placebo. A marked decrease in densitometric intensity ratios of amplified ACE cDNA to elongation factor-1
control cDNA was observed
in all tissues from placebo-treated rats compared with the
estradiol-treated rats (renal cortex: 0.29±0.04 versus 0.14±0.02;
renal medulla: 0.37±0.04 versus 0.24±0.03; lung: 4.49±0.37 versus
2.49±0.59; and aorta: 0.41±0.04 versus 0.29±0.02; all
P<0.05). A comparable reduction in ACE activity was
detected in tissue extracts from kidney cortex, kidney medulla, and
lung of hormone-treated animals. Incubation of purified rat lung ACE
with 1 or 10 µmol/L 17ß-estradiol had no effect on enzyme
activity. These results suggest that estrogen treatment regulates
tissue ACE activity by reducing ACE mRNA concentrations. Thus, the
beneficial cardiovascular effects of estrogen may be
mediated in part by downregulation of ACE with a consequent reduction
in the circulating levels of the vasoconstrictor
angiotensin II, a decrease in the metabolism of
the vasodilator bradykinin, and an increase in the production
of the vasorelaxant angiotensin-(1–7).
Key Words: angiotensin-converting enzyme • estrogen • gene regulation • hormone replacement • reverse transcriptase–polymerase chain reaction
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Introduction |
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Gender differences in the development of cardiovascular disease are documented in both animal and human studies. Cardiovascular disease is more prevalent in men than in premenopausal women, but the incidence increases sharply in perimenopausal women.1 2 Furthermore, estrogen replacement therapy reduces the risk of coronary artery disease in postmenopausal women, while young, bilaterally oophorectomized women have an increased occurrence of coronary disease.3 4 5 Thus, circulating endogenous estrogens are proposed to exert a cardioprotective effect, promoting the widespread recommendation for estrogen use in postmenopausal replacement therapy. The protective effect of estrogen is mediated, in large part, by modulating lipoprotein metabolism.3 4 6 Estrogens increased HDL cholesterol, decreased plasma LDL cholesterol, and attenuated oxidized LDL production.7 8 9 10 These actions effectively diminish accumulation of proatherogenic LDL in the arterial wall and reduce coronary artery atherosclerosis. While effects on lipid profiles account for a significant portion of the protective action of estrogen, differences in lipid levels do not entirely explain the influence of gender on the development of cardiovascular disease.
We previously showed that angiotensin-converting enzyme (ACE) activity is reduced in 2 models of postmenopausal chronic hormone replacement. ACE, a zinc-containing dipeptidyl carboxypeptidase (EC 3.4.15.1), is a key enzyme of the renin angiotensin system that plays an important role in the regulation of cardiac function and blood pressure.11 12 13 ACE is responsible for the local conversion of angiotensin I (Ang I) to the potent vasoconstrictor angiotensin II (Ang II). Ang II has a wide variety of effects on target organs of the cardiovascular system, including systemic and coronary artery vasoconstriction and stimulation of vascular smooth muscle cell growth.14 Conversely, bradykinin, a naturally occurring nonapeptide, is locally degraded by ACE.11 12 13 Bradykinin acts as a potent vasodilator of peripheral arteries by a variety of mechanisms, including the release of nitric oxide, prostaglandins, and endothelial-derived hyperpolarizing factor.15 16 In addition, angiotensin-(1–7) [Ang-(1–7)], which dilates coronary arteries through the release of nitric oxide or the potentiation of bradykinin effectiveness,17 18 is degraded and inactivated by ACE.19 Thus, a reduction in ACE activity leads not only to an attenuation of Ang II production and a decrease in bradykinin degradation but also to an increase in the vasodilator Ang-(1–7), an active metabolite of Ang I. ACE inhibitors are clinically effective in the treatment of hypertension and associated end-organ disease.12 13
We observed an attenuation of ACE activity in surgically induced postmenopausal cynomolgus monkeys treated with conjugated equine estrogen (Premarin) for 30 months.20 This reduction in ACE activity after estrogen treatment was associated with a significant increase in plasma Ang I and hyperreninemia but with a reduced formation of Ang II. Furthermore, estradiol replacement therapy decreased serum ACE activity in both ovariectomized normotensive and hypertensive (mRen2)27 transgenic rats, which contain an inserted mouse renin gene.21 Kidney and aorta tissue extracts from the hormone-treated transgenic rats also exhibited a significant reduction in enzyme activity. The effects of estrogen were associated with a moderation of the hypertension in the transgenic rats and a lowering of blood pressure in the normotensive animals. These results suggest that estrogen may mediate its cardioprotective effect in part by modulating ACE activity. This report is the first to show that estrogen treatment regulates the activity of ACE in tissues by reducing ACE mRNA concentrations.
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Animal Treatment
Bilateral oophorectomy was performed on 12-week-old Sprague-Dawley rats (220 to 225 g) under general anesthesia with ketamine (30 mg/kg IM) and xylazine (5 mg/kg IM). The ovariectomized rats were randomly divided into 2 groups, and pellets containing either 17ß-estradiol (5 mg per rat with a 3-week release; Innovative Research of America)22 or placebo were implanted in the subcutaneous tissue. After recovery, the rats were allowed free access to water and were fed standard rat chow. The animals were housed in individual cages and maintained at 22°C with 12 hours of light.
After 18 to 20 days, the rats were killed by decapitation, and trunk blood was collected into prechilled tubes for determination of serum 17ß-estradiol concentration and serum ACE activity. In addition, the kidneys, aorta, and lungs were harvested and dissected free of connective tissue on ice, and the kidney cortex and medulla were separated. The tissues were quick-frozen on dry ice and stored at –80°C until analyzed for ACE mRNA concentration and ACE activity.
17ß-Estradiol Measurement
Plasma estradiol concentrations were determined by
radioimmunoassay with the use of a commercially available kit
(Polymedco, Inc).
Reverse Transcriptase–Polymerase Chain Reaction Assay
Total RNA was isolated from the kidney, lung, and aorta of each
rat with the TRIZOL reagent (GIBCO BRL Products), as directed by
the manufacturer. The RNAs were processed and analyzed
separately. The RNA concentration was quantified by UV spectroscopy,
and any degradation was assessed by ethidium bromide staining intensity
of 28S and 18S ribosomal RNA after agarose gel electrophoresis. The RNA
was incubated with RQ1 DNase (Promega Corp) to eliminate any residual
DNA that would amplify during the polymerase chain reaction (PCR).
Approximately 250 ng of total RNA was incubated with or without avian
myeloblastosis virus (AMV) reverse transcriptase (RT) (Promega
Corp) in a mixture containing deoxynucleotides, random
hexamers, and RNase inhibitor in RT buffer.23
Heating the mixture for 5 minutes at 95°C terminated the
reaction.
For amplification of the resulting cDNA, 1 µmol/L gene-specific
primers, 0.2 mmol/L deoxynucleotides, 1.5 mmol/L
MgCl2, and 1.5 U Taq polymerase were
added to 3 µL of each RNA sample in a final volume of 50 µL. Primer
sequences were based on the sequences of the cloned ACE
gene24 25 and elongation factor-1 (EF1)
gene.26 Primer sets were as follows: ACE forward primer
5'-CAGCTTCATCATCCAGTTCC-3' and reverse primer
5'CTAGGAAGAGCAGCACCCAC-3', yielding an amplification product of 406
base pairs, and EF1 forward primer 5'-GGAATGGTGACAACATGCTG-3' and
reverse primer 5'CGTTGAAGCCTACATTGTCC-3', resulting in a 347–base pair
product. Any variations in reverse transcription or amplification
efficiency, RNA degradation, pipetting, or sample loading were detected
by the cotranscription and amplification of the positive control mRNA,
EF1, since ACE mRNA concentration was quantified as a ratio of the
amount of target cDNA/EF1 cDNA. The abundant, housekeeping
transcript EF1 was used as a positive control mRNA rather than
GADPH, a conventional standard, because previous studies showed that
GADPH mRNA is upregulated by Ang II.27 Approximately 5
µCi [32P]dCTP was also included in the
reaction for subsequent quantification of the amplification
products. Amplification conditions were as follows: denaturation at
94°C for 60 seconds; annealing at 62°C for 60 seconds; and
elongation at 72°C for 60 seconds for 28 cycles, with a final
elongation step at 72°C for 7 minutes. Primers for the control
EF1 sequence were added after 5 amplification cycles were completed.
After PCR, the amplification products were separated on a 6%
polyacrylamide gel and visualized by
autoradiography. Bands intensities were quantified with
the use of computerized densitometry (Micro Computer Imaging Device,
Imaging Research Inc).
A DNA sequence of amplified products was obtained during the development of the ACE RT-PCR assay and each time a new primer set was purchased. The sequence analysis as well as the molecular size of the amplified products confirmed accurate RT-PCR of the mRNAs of interest. In the development of the ACE RT-PCR assay, optimum amplification conditions and reagent concentrations were carefully determined. In addition, the cycle number was optimized for linear amplification, since a loss of linearity occurs with increased cycle number because of reagent depletion and reduced primer-annealing efficiency. False-positive signals produced by the introduction of contaminating DNA into this sensitive assay were detected in a complementary RT minus reaction.
Serum ACE Activity Assay
Serum ACE activity was measured with a commercially available
kit (Hycor). Duplicate aliquots of rat serum were incubated with the
tripeptide substrate
[3H]hippuryl-glycly-glycine for 60 minutes at
37°C. The reaction mixture was acidified, and the
[3H]hippuric acid released by the enzyme was
extracted into ethyl acetate with >90% recovery. The concentration of
the liberated [3H]hippuric acid was quantified
by liquid scintillation spectrometry.
Tissue ACE Activity Assay
Approximately 250 to 300 mg (wet weight) of kidney cortex,
kidney medulla, or lung tissue was minced and homogenized
with the use of a Teflon-glass homogenizer in 3.0 mL of
extraction buffer (10 mmol/L HEPES, pH 7.4, containing 125
mmol/L NaCl). The cellular membranes were isolated by
centrifugation at 12 000g for 20 minutes at
4°C and rehomogenized in 3.0 mL of extraction buffer. The
membrane fraction was isolated by a second
centrifugation, and the resultant pellet was
resuspended in 3.0 mL of extraction buffer by
homogenization. Protein content of the membrane
fraction was determined by the method of Lowry et
al28 using bovine serum albumin as a
standard. Aliquots of the resuspended membranes were incubated with
30 mmol/L Hip-His-Leu for 15 minutes at 37°C. The ACE
inhibitor lisinopril (1 µmol/L) was
added to a second set of aliquots as a control for ACE specificity.
Enzyme activity was quantified by fluorometric measurement of hippurate
cleavage from the substrate and compared with standards.
17ß-Estradiol Treatment of Purified ACE
ACE was isolated from a membrane fraction of rat lung with the
use of a lisinopril-coupled affinity column, as previously
described.19 A single band corresponding to the 170-kDa
somatic ACE was obtained after polyacrylamide gel
electrophoresis, indicating the high degree of purity of the enzyme
preparation.
Aliquots of the purified enzyme were incubated with 30 mmol/L Hip-His-Leu and 1 or 10 µmol/L 17ß-estradiol for 15 minutes at 37°C. A mixture without 17ß-estradiol served as a control. The ACE inhibitor lisinopril (1 µmol/L) was added to a second set of aliquots as a control for ACE specificity. Enzyme activity was quantified by fluorometric measurement of hippurate cleavage from the substrate and compared with standards.
Statistical Analysis
Data are expressed as mean±SEM. Differences between groups were
compared with Student's t test for unpaired data.
Statistical significance was accepted with probability value
<0.05.
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17ß-Estradiol Concentration in Ovariectomized Rats
A radioimmunoassay was used to verify an increase in plasma 17ß-estradiol from ovariectomized Sprague-Dawley rats treated for 18 to 20 days with implanted pellets continuously releasing hormone compared with control animals. The concentrations averaged 894±114 pg/mL in 17ß-estradiol–treated rats (n=8) and <15 pg/mL in placebo-treated animals (n=8; P<0.05 compared with treated rats).
Effect of Hormone Replacement on ACE mRNA Concentration
Total RNA was isolated from the kidney cortex, kidney medulla,
lung, or aorta of Sprague-Dawley rats after 3 weeks of 17ß-estradiol
treatment or placebo to determine whether hormone replacement regulates
ACE mRNA concentration. An autoradiogram typical of a
RT-PCR determination for kidney cortex and medulla is shown in Figure 1A
. A marked decrease in band intensities
corresponding to ACE mRNA was observed in both kidney cortex and kidney
medulla samples from hormone-treated rats compared with controls.
Autoradiograms of RT-PCR analysis of lung or
aorta mRNA isolated from rats after 17ß-estradiol treatment or from
placebo controls showed similar patterns (Figures 2A and 3A,
respectively).
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Densitometric intensity ratios of amplified ACE cDNA to EF1 control
cDNA significantly decreased in the kidney cortex (0.29±0.04 versus
0.14±0.02; Figure 1B
) and kidney medulla (0.37±0.04 versus
0.24±0.03; Figure 1B) of controls compared with the
estradiol-treated rat samples. Three weeks of hormone replacement
therapy also induced a 1.8-fold decrease in ACE mRNA concentrations in
the rat lung (4.49±0.37 versus 2.49±0.59; Figure 2B) from
hormone-treated rats compared with controls. A similar reduction in ACE
transcript concentration (0.41±0.04 versus 0.29±0.02; Figure 3B) was observed in samples isolated from the aortas of
estradiol-treated rats.
Effect of Hormone Replacement on Serum and Tissue ACE
Activity
ACE activity was measured in tissue homogenates of
placebo- and estradiol-treated rats to verify that reduced ACE mRNA
correlated with decreased enzyme activity. As shown in Figure 4, ACE activity was attenuated in tissue
extracts from kidney cortex (2.01±0.28 versus 1.24±0.16 nmol/mg per
minute), kidney medulla (1.52±0.23 versus 0.86±0.13 nmol/mg per
minute), and lung (58.31±6.58 versus 34.62±4.25 nmol/mg per minute)
after 3 weeks of 17ß-estradiol treatment compared with placebo
controls. Serum ACE activity decreased from 98.8±6.8 nmol/mL per
minute (n=8) to 71.0±5.7 nmol/mL per minute (n=8; P<0.05)
with hormone replacement. In contrast, incubation of purified rat lung
ACE with 1 or 10 µmol/L 17ß-estradiol did not reduce the
enzyme activity (data not shown).
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Our studies demonstrate for the first time that estrogen treatment modulates ACE mRNA concentration in rat kidney, lung, and aorta, with a resultant attenuation of ACE activity. The reduction in ACE activity was not due to a direct interaction of estrogen with the enzyme. These results suggest that the cardioprotective properties of estrogen are due in part to the diminished ACE activity in vivo through inhibition of ACE mRNA synthesis. These findings support further studies of chronic hormone replacement therapy for therapeutic intervention.
We previously showed that ACE activity is reduced in 2 models of
postmenopausal chronic hormone replacement: ovariectomized monkeys
treated with conjugated equine estrogen (Premarin) for 30
months20 and ovariectomized normal and transgenic rats on
3 weeks of estradiol replacement therapy.21 In our
previous publication,21 we used an estrogen dose (1.5
mg/rat for a 3-week release) that raised the levels of circulating
estrogen to 150 to 190 pg/mL. This 17ß-estradiol concentration was
characterized as a physiological dose during the
estrous or menstrual cycle29 30 or after hormone
replacement.31 This dose reduced the levels of plasma ACE
in both Sprague-Dawley and transgenic rats by 40% to
50%.21 In the present studies we used a higher dose
of estrogen (5 mg/pellet), which raised the circulating 17ß-estradiol
slightly more than 4-fold (to 894 pg/mL) and decreased the circulating
levels of ACE activity 
30%. Thus, both the higher and lower doses
of 17ß-estradiol had nearly equivalent effects on circulating ACE
activity.
Studies by other investigators also showed that ACE activity is regulated by estrogen. Seltzer et al32 demonstrated that estrogen administration to ovariectomized rats reduced ACE activity in the anterior pituitary. No change in pituitary or circulating ACE activity was detected with the normal estrus cycle, suggesting that attenuated ACE activity occurs only after chronic exposure to estrogen at doses in excess of endogenous concentrations. Furthermore, pituitary ACE from ovariectomized rats treated with estradiol showed a decreased Vmax compared with controls, indicating that estrogen may reduce ACE production. Female mice homozygous for the ACE gene have 60% lower plasma ACE activity compared with males, indicating a sexual dimorphism.33 Serum ACE activity was also reduced in the first and second trimesters in normotensive pregnant women with elevated plasma estrogen compared with nonpregnant subjects.34 35 In addition, postmenopausal women on estrogen hormone replacement showed a slight but significant lower serum ACE activity compared with those without hormone replacement.36 Because androgens have no effect on somatic ACE activity,37 these findings suggest that the sexual dimorphism for ACE activity between males and females may be due in part to estrogen-induced reduction of ACE mRNA and ACE activity.
Estrogens, like all members of the steroid family of hormones, regulate cellular processes through specific hormone receptor–mediated mechanisms.38 The estrogen-receptor complex regulates transcription of a variety of genes by binding to estrogen response elements and affecting RNA polymerase activity. Such directly activated genes are referred to as primary response genes. Many of the estrogen-regulated, primary response genes encode transcription factors. The estrogen-receptor complex also mediates gene transcription independent of its hormone response element. By this mechanism, the estrogen-receptor complex interacts directly with transcription factors, forming a multiprotein complex that binds to specific gene response elements. For example, the estrogen-receptor complex will bind with a Fos and Jun heterodimer and affect gene transcription at an AP1 site.39 40 41 Thus, estrogen mediates its regulatory effects by multiple, cascading mechanisms.
No estrogen response element (5'-GGTCANNNTGACC-3') was reported in the 5' flanking region of the ACE coding sequence; however, the ACE promoter does contain a consensus AP1 site in the 300–base pair region upstream from the start site.42 43 44 45 It is possible that the ACE mRNA regulation by estrogen treatment occurs through a receptor-mediated complex interaction with the Fos-Jun heterodimer at an AP1 site. Estrogen also binds to imperfect estrogen response elements, albeit with lower affinity, by forming heterodimers with nonhormone proteins or through other protein-protein interactions. Thus, additional analyses of the regulatory regions of the ACE gene are needed to elucidate the precise molecular mechanism of the regulation of ACE mRNA by estrogen.
In summary, it is known that estrogen causes overexpression of both tissue and circulating concentrations of angiotensinogen46 47 and renin.48 49 50 51 Conversely, the present study shows that estrogen treatment reduces ACE mRNA and ACE activity. These results, in conjunction with previous studies from our laboratory, demonstrate that the reduction in ACE mRNA and ACE activity is associated with a decrease in plasma Ang II, an increase in the vasodilator peptide Ang-(1–7), and an attenuation in blood pressure.20 21 Thus, estrogen replacement therapy, by acting at a later step in the renin-angiotensin system cascade, may contribute to enhanced cardiovascular protection by downregulating ACE mRNA concentrations, thereby reducing ACE activity. This would cause an attenuation in the production of the vasoconstrictor Ang II and an increase in the vasorelaxants bradykinin and Ang-(1–7), all of which produce favorable cardiovascular effects.
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Acknowledgments |
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This work was supported in part by grant HL-56973 from the National Institutes of Health and a Grant-in-Aid from the North Carolina affiliate of the American Heart Association. The authors thank Drs E. Ann Tallant and Randi B. Weiss for helpful discussion and Nancy Pirro for expert technical assistance.
Received September 17, 1998; first decision October 14, 1998; accepted October 30, 1998.
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