(Hypertension. 1997;30:128-133.)
© 1997 American Heart Association, Inc.
Articles |
Blood Pressures and Cardiovascular Homeostasis in Mice Having Reduced or Absent Angiotensin-Converting Enzyme Gene Function
From the Vascular Biology and Hypertension Program of the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham (B.T., Q.C.M., Y.-F.C., S.O.), and Departments of Internal Medicine (J.H.K.) and Pathology (J.H.K., O.S.), University of North Carolina at Chapel Hill.
Correspondence to Suzanne Oparil, MD, 1034 Zeigler Building, 703 S 19th St, University of Alabama at Birmingham, Birmingham, AL, 35294-0007. E-mail card027{at}uabdpo.dpo.uab.edu
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Abstract |
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Abstract We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivation of the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/- mice but was reduced by 51±4 mm Hg in -/- mice. Although the pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by Ace genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/- group and virtually abolished (+1%) in the -/- group. The depressor response to injected bradykinin was significantly enhanced in the +/- and -/- groups compared with the +/+ group. Ace expression and ACE activity were directly related to functional Ace copy number, and renin and angiotensinogen mRNA levels were inversely related to Ace copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the +/+, +/-, and -/- groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one Ace copy, which include increased expression of renin, normalize blood pressure in heterozygotes.
Key Words: gene targeting • renin • angiotensin I • angiotensin II • bradykinin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase (EC 3.4.15.1) that plays an important role in the regulation of BP and determination of cardiac and vascular structure through at least two mechanisms: conversion of the biologically inactive decapeptide Ang I to the potent vasoconstrictor and mitogenic octapeptide Ang II and degradation of the vasodilator/antimitogenic peptide BK into inactive fragments.1 Inhibition of ACE with specific inhibitors reduces BP in hypertensive patients with high, normal, or low renin levels and prevents or reverses cardiac hypertrophy of various causes, including hypertension, ischemic heart disease, and heart failure.2 3 4 In contrast, ACE inhibitors do not lower BP in sodium-replete normotensive subjects.5
Induced-mutation technology has provided a new way of studying the genetics of complex diseases. Ace is composed of two homologous regions and codes for both a larger somatic and smaller testis isoenzyme.6 7 8 Krege et al9 used gene targeting to insertionally disrupt exon 14 of Ace in order to inactivate both ACE isozymes. Serum ACE activity was reduced in heterozygous mice and was undetectable in homozygous mutant mice. Compared with +/+, the -/- mice had BP levels reduced by about 34 mm Hg, hyperplastic renal vasculature associated with renal cortical atrophy, and reduced fertility in males. The current study has extended these observations by characterizing in +/+, +/-, and -/- mice the effects of reduced levels or absence of ACE on baseline BP; on BP responses to injected Ang II, Ang I, and BK; and on steady-state mRNA levels for angiotensinogen, renin, ACE, and AT1A receptors.
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Methods |
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Generation of Mice
F2 mice (strain 129/OlaxC57BL/6J) +/- and +/+ for an insertional disruption of exon 14 of Ace9 were produced at the University of North Carolina at Chapel Hill. Offspring of mating +/+ or +/- F2 males with +/- F2 females were produced at the University of Alabama at Birmingham Animal Research Center.
At age 21 days, mice were weaned and genotyped for Ace as described.9 Animals were provided chow (Teklad LM-485 sterilizable mouse diet) and water ad libitum and were maintained on a 12-hour light/dark cycle. Experiments were approved by the Institutional Animal Care and Use Committee at the University of Alabama at Birmingham and were consistent with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985).
Assessment of Baseline BP and BP Responses to Infusions of ACE
Substrates
Two major aims of our studies were to compare the baseline BPs
of normal +/+ mice with those having reduced (+/-) or absent (-/-)
ACE and to determine whether genetically altered levels of ACE affect
the BP responses to infusions of its substrates, Ang I and BK. Mice
weighing approximately 25 to 30 g were anesthetized with
intraperitoneal injections of a mixture of
ketamine (100 mg/kg, Parke-Davis) and xylazine (15 mg/kg, Sigma
Chemical Co). The carotid artery and jugular vein were exposed and
cannulated with polyethylene cannulas (PE-10 fused to PE-50 tubing,
Becton Dickinson) containing 50 U/mL heparin in saline. These cannulas
were passed under the skin and out through the nape and fixed with
dental acrylic (Dental Manufacturing Co). All incisions were then
ligated and the mice returned to individual cages and allowed at least
5 hours of recovery from anesthesia before the experiments
were begun. BP (mean arterial pressure) was measured in
conscious, unrestrained mice through the carotid artery cannula
connected to a pressure transducer. The jugular vein cannula was used
for intravenous injections. Data were collected with the
computer-assisted Acknowledge Workstation System (Biopac Systems,
Inc).
Ang II and Ang I (Sigma) at doses of 0.01, 0.1, and 1.0 µg/kg and BK (Sigma) at a dose of 5.0 µg/kg were dissolved in sterile saline solution (0.9% NaCl; total volume, 50 µL) immediately before each experiment. Peptides were injected through the jugular vein. The total volume of each injection was limited to 50 µL. The vehicle control was 50 µL saline. Hemodynamic parameters were allowed to return to normal between each injection, with a minimum of 10 minutes between injections.
ACE Activities
ACE circulates in plasma and is also present within many
tissues. To determine the effects of the Ace mutation on ACE
activities, we quantified ACE activity of plasma and tissues from +/+,
+/-, and -/- mice with reversed-phase high performance
liquid chromatography (HPLC) combined with a
spectrophotometric assay.10 This method is a modification
of the procedure of Cushman and Cheung,11 which uses the
artificial substrate hippuryl histidyl leucine (HHL) and quantifies the
product hippuric acid (HA) by UV detection at 228 nm. According to
this method, ACE is extracted from homogenized tissues with
detergent, and the reaction product HA is isolated from the
reaction mixture by reversed-phase HPLC, thus eliminating interference
from the detergent, the substrate HHL, and unreacted reaction
by-products. The active site-specific ACE inhibitor
captopril is used to inhibit the enzyme in blank samples and increase
the specificity of the assay. Data were expressed as units of HA formed
per milliliter plasma or per gram tissue (1 U=1 mmol HA formed per
minute at 37°C).
After mice were decapitated, blood was collected into iced tubes containing heparin (100 U/10 µL). Approximately 500 µL blood (200 µL plasma) was collected from each mouse. Plasma was separated and stored at -80°C until assay as described above.
Analysis of RNA
To study to what extent the genes of the
renin-angiotensin system respond to and compensate for the
Ace mutation, we quantified the steady-state transcript
levels of genes of the renin-angiotensin system in +/+,
+/-, and -/- mice. Lungs, hearts, kidneys, livers, and brains were
removed, rapidly frozen in liquid nitrogen, and stored at -70°C.
Total RNA was isolated using guanidinium isothiocyanate.12
The amount and purity of RNA were assessed by spectrophotometry.
Fifteen micrograms of total RNA was electrophoresed on 1.2% agarose
gels containing 6.6% formaldehyde in 20 mmol/L
3-(N-morpholino)propanesulfonic acid (MOPS), 5 mmol/L
sodium acetate, and 1 mmol EDTA, pH 7.0. The RNA was then blotted
to a positively charged Nytran Plus membrane (Schleicher & Schuell Inc)
by overnight capillary transfer and cross-linked to the membrane by UV
radiation. The probes used for these studies include a mouse cDNA probe
ACE.316 and rat cDNA probes for renin,13
angiotensinogen,14 and
AT1A.15 Probes were labeled with
[
-32P]dCTP by random labeling (Promega, Prime-a-Gene
Labelling System). Prehybridization and hybridization were performed in
QuickHyb hybridization buffer (Stratagene) at 68°C. After
hybridization, membranes were washed twice for 15 minutes in 0.1%
SDS/2x SSC at room temperature and once for 10 minutes in 0.1%
SDS/0.1x SSC at 55°C, and the results were visualized by
autoradiography. Loading of RNA was assessed by
rehybridization with a cDNA probe for 18S rRNA. Relative amounts of
mRNAs were quantified by densitometric scanning of the autoradiograph
with a computer-assisted imaging system (GS-670 Imaging Densitometer,
Bio-Rad).
Statistical Analysis
All data are presented as mean±SEM. Differences between
groups were assessed by ANOVA with post hoc analysis by
Student-Newman-Keuls test using SigmaStat software (Jandel Scientific
Software). Results were considered significant at a level of
P<.05.
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Results |
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Because a common polymorphism of human ACE is associated with changes in circulating ACE activities and may confer differential risk for cardiovascular diseases, we studied cardiovascular parameters in normal (+/+) mice and in mice having a genetically determined reduction (+/-) or absence (-/-) of normal Ace function. Matings of +/- males with +/- females yielded fewer +/- and -/- mice than predicted (41 +/+, 65 +/-, 14 -/-; ratio, 1:1.58:0.34). A similar reduction in +/- and -/- mice for the Ace mutation was previously observed by Krege et al.9
To determine whether a reduction or absence of ACE affects resting BPs
or the BP responses to infusions of its substrates, we measured basal
BP and HR as well as BP and HR responses to injected Ang II, Ang I, and
BK in +/+, +/-, and -/- mice (Figs 1 through 4
). Basal BP and HR did
not differ between the normal +/+ mice and the +/- mice that had
reduced Ace function. The -/- mice had a significantly
lower basal BP (approximately 50% of normal) and a tendency
(P=.09) toward a higher HR compared with the +/+ and +/-
mice (Fig 1). Intravenous injection of
graded doses of Ang II induced essentially indistinguishable
dose-dependent increases in BP and decreases in HR in all three groups
(Fig 2). However, and most importantly, the pressor and
HR responses to intravenous injection of graded doses of
Ang I were significantly reduced in the +/- mice and were virtually
absent in the -/- mice (Fig 3).
Intravenous injection of BK resulted in a depressor
response that was significantly (P<.01) greater in both
magnitude and duration in the -/- and +/- mice than in the +/+ mice
(Fig 4). Thus, the pressor responses to Ang I were
directly related (P<.0001) to functional Ace
copy number, and the depressor responses to BK were inversely related
(P<.01) to functional Ace copy number.
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To determine the effects of Ace genotype on tissue
and plasma ACE enzymatic activities, we measured ACE activities in
heart, lung, kidney, brain, and plasma of +/+, +/-, and -/- mice
(Fig 5). ACE activities were highest in kidney and lung,
much lower in heart and plasma, and were not detectable in brain.
Compared with +/+, ACE activities were reduced to approximately 40% of
normal in all organs of the +/- mice. ACE or ACE-like activities were
present at very low levels in tissues of -/- mice.
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ACE mRNA was expressed at the highest levels in lung, second highest in
kidney, and was detectable in heart and brain of +/+ mice by Northern
blot analysis (Fig 6). Ace expression
in +/- mice was approximately half that in +/+ mice in heart, lung,
and kidney. ACE mRNA appeared to be detectable at low levels (5% to
10%) in the tissues of -/- and +/- mice, although the mRNA was of
slightly smaller size (Fig 6) and also hybridized to a
neomycin-resistance gene probe (data not shown). The transcript most
likely represents upstream Ace gene sequences
reading into and terminating at the end of the neomycin-resistance gene
that was inserted into exon 14 of the Ace
gene.9 Steady-state ACE mRNA levels in the brains of all
mice were very low (<3% of the lung levels). These data demonstrate
that the +/- mice had steady-state levels of Ace mRNA
transcripts reduced to about 50% of normal in most tissues and that
Ace -/- mice have low levels of ACE mRNA transcripts that
are reduced in size and include a read through of the
neomycin-resistance gene that was inserted in exon 14 of
Ace.9
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To determine how the other genes of the renin-angiotensin
system respond transcriptionally to reduced or absent ACE, we used
Northern analysis to measure steady-state mRNA levels for
angiotensinogen in the liver, renin in the kidney, and
AT1A receptor in multiple tissues. Compared with the +/+
group, angiotensinogen gene expression in liver was
significantly increased in -/- but not +/- mice (Fig 7). Renal renin mRNA was increased to about 4 times
normal in +/- mice and to more than 100 times normal in -/- mice
(Fig 7). Relative AT1A gene transcript levels were not
significantly different in +/+, +/-, and -/- mice (Fig 8).
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Discussion |
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To study the role of Ace in BP control and cardiovascular homeostasis, we have examined cardiovascular phenotypes in normal mice and in mice having reduced or absent normal Ace function. To do this, we bred mice having a targeted disruption of Ace to generate +/+, +/-, and -/- mice. We studied -/- mice lacking normal Ace function to determine whether ACE is essential in the tonic control of BP and for normal BP responses to infusions of its substrates. Also, because a spontaneously occurring insertion (I)–deletion (D) polymorphism in intron 16 of human ACE is associated with quantitative differences in serum ACE activities, we studied the cardiovascular effects of changes in the quantitative level of Ace function in +/+ and +/- mice. Finally, we determined the transcriptional adaptations that occur in the presence of a reduction in or absence of normal Ace function.
The -/- mice, which we demonstrated have very low levels of ACE or ACE-like activity and low levels of a truncated ACE mRNA, have BP levels reduced to about 50% of normal, show virtually no response to injected Ang I, and give an augmented response to infused BK. These findings indicate that Ace is essential in the tonic control of BP and for normal BP responses to infusions of its substrates. Significant reductions in BP have been previously reported in studies of mice lacking the genes for angiotensinogen16 17 or AT1A receptor,18 19 confirming the essential importance of the genes of the renin-angiotensin system in normal BP control.
In contrast, basal BP levels in +/- mice were not significantly different from those in +/+ mice. This observation that normal BP is maintained in the presence of changes in the quantitative level of Ace function is consistent with the weight of evidence from a variety of other studies. In humans, association of the ACE D allele with hypertension has been observed in some20 21 22 but not other23 24 25 26 case-control association studies of hypertension but in zero of nine case-control studies primarily of atherosclerosis or myocardial infarction.27 28 29 30 31 32 33 34 35 The only sib-pair linkage study of ACE did not find significantly increased sharing of markers linked to human ACE in siblings that shared hypertension.36 In one study, an association was found between the ACE I allele and hypertension37 and was hypothesized to be a result of age-related loss of D alleles.38
The finding that basal BP levels in +/- mice were not significantly different from those in +/+ mice suggests the possibility that the quantitative level of Ace function is not important for BP regulation. To investigate this possibility further, we determined whether quantitative changes in the level of Ace function materially affect the pressor and depressor responses to injections of its substrates, Ang I and BK, and of its product, Ang II. Compared with +/+ mice, we found in +/- mice that the pressor responses to injected Ang I were attenuated, the depressor responses to BK were enhanced, and the BP responses to Ang II were preserved but not augmented. These data indicate that the level of Ace function does significantly affect the BP responses to injections of its substrates but not of its product and provide sufficient evidence for us to reject the hypothesis that quantitative variation in the level of Ace gene function is physiologically unimportant.
In comparing +/+ and +/- mice, our findings that the basal BP levels were not significantly different but that the BP responses to infused Ang I and BK were significantly different suggested to us that compensatory adaptations might be occurring in the +/- mice, which are normal and unstressed in all respects except in their Ace function. We therefore evaluated the +/- mice for the presence of compensatory adaptations in the transcription of the remaining functional Ace allele and in other genes of the renin-angiotensin system. We found that the ACE mRNA levels and ACE activities were about 40% to 50% of normal in +/- mice, indicating that the remaining wild-type Ace allele in the +/- mice does not compensate for disruption of the Ace allele on the other chromosome. Importantly, however, mice +/- for the Ace disruption have increased renal renin mRNA levels. Thus, compensations for reduced Ace function, including increased expression of renin, occur in the +/- mice and normalize their BP levels.
Our findings lead us to several interesting conclusions. First, Ace is essential for the maintenance of normal BP and for normal BP responses to injected Ang II and BK. Second, the absence of BP differences between the otherwise normal +/+ and +/- mice leads us to conclude that quantitative variation in Ace function does not observably affect basal BP in the absence of other environmental or genetic factors. Third, our observations of differences between +/+ and +/- mice in their responses to injected Ang I and BK indicate that quantitative variation in Ace function does nevertheless materially affect the in vivo metabolism of ACE substrates. Fourth, our observation of increased expression of renin in +/- compared with +/+ mice leads us to conclude that compensatory adaptations are present in +/- mice and that these compensatory adaptations successfully normalize their BP levels. Finally, our overall results suggest the possibility that quantitative changes in expression of Ace will observably affect BP when accompanied by additional changes in either other genes or other environmental factors that, acting synergistically with Ace, stress the compensatory mechanisms beyond their limits.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-44195 and HL-50147 to Y.-F.C., HL-47081 and HL-07457 to S.O., HL-49277 and GM-20069 to O.S., and HL-03470 to J.H.K. J.H.K. was a Howard Hughes Physician Post-Doctoral Fellow. The authors thank Beverly Caver for her assistance in the preparation of this manuscript.
Received September 17, 1996; first decision October 15, 1996; accepted November 25, 1996.
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 K. R. Santhamma, R. Sadhukhan, M. Kinter, S. Chattopadhyay, B. McCue, and I. Sen Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme J. Biol. Chem., September 17, 2004; 279(38): 40227 - 40236. [Abstract] [Full Text] [PDF]
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S. P. Kessler, P. deS. Senanayake, T. S. Scheidemantel, J. B. Gomos, T. M. Rowe, and G. C. Sen Maintenance of Normal Blood Pressure and Renal Functions Are Independent Effects of Angiotensin-converting Enzyme J. Biol. Chem., May 30, 2003; 278(23): 21105 - 21112. [Abstract] [Full Text] [PDF]
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 T. E. Scholzen, S. Stander, H. Riemann, T. Brzoska, and T. A. Luger Modulation of Cutaneous Inflammation by Angiotensin-Converting Enzyme J. Immunol., April 1, 2003; 170(7): 3866 - 3873. [Abstract] [Full Text] [PDF]
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J. M. Cole, N. Khokhlova, R. L. Sutliff, J. W. Adams, K. M. Disher, H. Zhao, M. R. Capecchi, P. Corvol, and K. E. Bernstein Mice Lacking Endothelial ACE: Normal Blood Pressure With Elevated Angiotensin II Hypertension, February 1, 2003; 41(2): 313 - 321. [Abstract] [Full Text] [PDF]
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 C.-C. Wei, B. Tian, G. Perry, Q. C. Meng, Y.-F. Chen, S. Oparil, and L. J. Dell'Italia Differential ANG II generation in plasma and tissue of mice with decreased expression of the ACE gene Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2254 - H2258. [Abstract] [Full Text] [PDF]
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S. P. Kessler, J. B. Gomos, T. S. Scheidemantel, T. M. Rowe, H. L. Smith, and G. C. Sen The Germinal Isozyme of Angiotensin-converting Enzyme Can Substitute for the Somatic Isozyme in Maintaining Normal Renal Structure and Functions J. Biol. Chem., February 1, 2002; 277(6): 4271 - 4276. [Abstract] [Full Text] [PDF]
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S. H. Carlson, S. Oparil, Y.-F. Chen, and J. M. Wyss Blood Pressure and NaCl-Sensitive Hypertension Are Influenced by Angiotensin-Converting Enzyme Gene Expression in Transgenic Mice Hypertension, February 1, 2002; 39(2): 214 - 218. [Abstract] [Full Text] [PDF]
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 S.B. GURLEY, T.H. LE, and T.M. COFFMAN Gene-targeting Studies of the Renin-Angiotensin System: Mechanisms of Hypertension and Cardiovascular Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 451 - 458. [Abstract] [PDF]
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 B. C. Cholewa and D. L. Mattson Role of the renin-angiotensin system during alterations of sodium intake in conscious mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R987 - R993. [Abstract] [Full Text] [PDF]
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 G. J. Perry, T. Mori, C.-C. Wei, X. Y. Xu, Y.-F. Chen, S. Oparil, P. Lucchesi, and L. J. Dell'Italia Genetic Variation in Angiotensin-Converting Enzyme Does Not Prevent Development of Cardiac Hypertrophy or Upregulation of Angiotensin II in Response to Aortocaval Fistula Circulation, February 20, 2001; 103(7): 1012 - 1016. [Abstract] [Full Text] [PDF]
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 N. E. S. Sibinga and J. A. Ware A Pair of ACEs, for Openers? Circ. Res., September 29, 2000; 87(7): 523 - 525. [Full Text] [PDF]
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T. Rankinen, J. Gagnon, L. Perusse, Y. C. Chagnon, T. Rice, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H368 - H374. [Abstract] [Full Text] [PDF]
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 T. Rankinen, L. Perusse, J. Gagnon, Y. C. Chagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard Angiotensin-converting enzyme ID polymorphism and fitness phenotype in the HERITAGE Family Study J Appl Physiol, March 1, 2000; 88(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
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 L. CERVENKA, K. D. MITCHELL, and L. G. NAVAR Renal Function in Mice: Effects of Volume Expansion and AngiotensinII J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2631 - 2636. [Abstract] [Full Text]
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 T. Traynor, T. Yang, Y. G. Huang, J. H. Krege, J. P. Briggs, O. Smithies, and J. Schnermann Tubuloglomerular feedback in ACE-deficient mice Am J Physiol Renal Physiol, May 1, 1999; 276(5): F751 - F757. [Abstract] [Full Text] [PDF]
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D. L. Mattson and K. R. Krauski Chronic Sodium Balance and Blood Pressure Response to Captopril in Conscious Mice Hypertension, November 1, 1998; 32(5): 923 - 928. [Abstract] [Full Text] [PDF]
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 P. A Doevendans, M. J. Daemen, E. D de Muinck, and J. F Smits Cardiovascular phenotyping in mice Cardiovasc Res, July 1, 1998; 39(1): 34 - 49. [Abstract] [Full Text] [PDF]
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S. P. Kessler, T. M. Rowe, J. B. Gomos, P. M. Kessler, and G. C. Sen Physiological Non-equivalence of the Two Isoforms of Angiotensin-converting Enzyme J. Biol. Chem., August 18, 2000; 275(34): 26259 - 26264. [Abstract] [Full Text] [PDF]
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