(Hypertension. 1997;29:1104-1108.)
© 1997 American Heart Association, Inc.
Articles |
Distinct Mechanisms of Modulation of Angiotensin II Type I Receptor Gene Expression in Heart and Aorta
From the Department of Internal Medicine, Hypertension and Vascular Research Laboratories, University of Texas Medical Branch, Galveston.
Correspondence to Donna H. Wang, MD, Department of Internal Medicine, Hypertension and Vascular Research Laboratories, 8.104 Medical Research Building, University of Texas Medical Branch, Galveston, TX 77555-1065. E-mail dwang%intmeds1{at}mhost.utmb.edu
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Abstract |
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Abstract The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT1) in the thoracic aorta and heart through an Ang II–dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT1 to GAPDH mRNA in the aorta was significantly higher in RRM (1.85±0.52) compared with sham-operated (0.21±0.04) and RRM+Cap (0.55±0.20) rats. In contrast, the ratio of AT1 to GAPDH mRNA in the heart was significantly increased in both RRM (1.09±0.23) and RRM+Cap (1.00±0.09) compared with sham-operated (0.34±0.06) rats. Thus, RRM hypertension upregulates AT1 mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT1 mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT1 gene regulation exist; ie, in aorta, an Ang II– or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT1 mRNA may be pressure dependent.
Key Words: aorta • hypertension, reduced renal mass • receptors, angiotensin II • heart • captopril
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Introduction |
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Although plasma renin and Ang II levels are low in RRM hypertensive rats as well as in some other renal hypertensive models, considerable circumstantial evidence demonstrates that ACE inhibitors attenuate cardiac and vascular hypertrophy to a greater extent than would be expected from their effect on systemic BP alone.1 2 3 4 These observations suggest that the local tissue RAS may be activated and play an important role in the abnormal growth of cardiovascular tissues in these hypertensive models.
A role for the local RAS in the abnormal growth of cardiac or vascular tissues would require an increase in either the synthesis of the RAS components or the binding affinity of Ang II for its receptor, or the geneexpression or number of receptors in these tissues. However, it has been shown that local synthesis of RAS components in the heart is not increased in RRM rats because cardiac tissue Ang II levels are decreased in cases of RRM hypertension.4 We therefore propose that the gene expression or number of Ang II receptors in the heart of RRM rats is increased. Although there have been many studies on the regulation of cardiovascular Ang II receptor protein (for review, see Reference 55 ), relatively little is known regarding the regulation of Ang II receptor gene expression. The study of the abnormality in the expression and regulation of the AT1 receptor in the cardiovascular tissues of RRM rats may provide insight into the pathophysiological basis for the abnormality in BP and tissue growth because we know that elevated BP and hypertrophy of the tissues in this model are not mediated by the circulating Ang II. We and others have previously demonstrated that AT1 receptor gene expression is regulated by a variety of physiological and pathophysiological conditions6 7 in the kidney and adrenal gland. In the present experiments, we tested the hypothesis that AT1 receptor gene expression is upregulated in the heart and aorta of low-renin RRM hypertensive rats. Because we have shown that Ang II exerts feedback regulation on expression of the gene encoding the AT1 receptor in the adrenal gland,8 the second hypothesis we tested was that inhibiting the RAS, and thus Ang II generation, with captopril without decreasing BP in RRM hypertensive rats would inhibit AT1 gene expression in the heart and aorta.
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Methods |
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Animal Groups
Eleven-week-old male Wistar rats (Charles River Laboratories Inc, Wilmington, Mass) weighing 325 to 350 g were anesthetized with a single intraperitoneal injection of 80 mg/kg ketamine and 1 mg/kg xylazine and subjected to RRM (n=5), RRM plus captopril (RRM+Cap, n=5), or sham surgery (n=5). Surgical renal reduction was performed by removing the right kidney and the two poles of the left kidney as described previously.9 10 11 The total renal mass removed was approximately 75%. After surgery, the rats were given 1% NaCl in their drinking water ad libitum to trigger the development of hypertension. Captopril (30 mg/kg per day, a generous gift from Bristol-Myers Squibb Co) was dissolved in 0.5 to 1 mL water and given by oral gavage three times per day. It has been shown that the above drug dose does not decrease BP in RRM hypertension but does prevent the BP rise in response to exogenously injected Ang I.12 An equal amount of water was given by the same method to both the RRM and sham-operated rats. At the end of the 12-day treatment period, all rats were anesthetized with the same dose of ketamine and xylazine as described above and the carotid artery was catheterized for measurement of mean arterial pressure. Mean arterial pressure responses to bolus injections of Ang I (150 ng/kg) and Ang II (150 ng/kg) were assessed in all three rat groups to evaluate the effectiveness of captopril treatment. All animal procedures were in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.
Systolic BP
Indirect tail-cuff systolic BPs were routinely obtained
in all rats with a Gould 2400S recorder connected to a Narco
BioSystems Electro-Sphygmomanometer. Pressures were measured in
conscious rats every 3 days for 12 days, beginning 1 day before the
surgery. The BP value for each rat was calculated as the average of
three separate measurements at each session.
Tissue Preparation
At the end of the treatment period and with rats under
anesthesia, a midline incision was made on the chest and
the heart was removed and weighed. About 5 mm of thoracic aorta
right below the aortic arch was carefully removed and fixed in 4%
paraformaldehyde/phosphate-buffered saline, pH 7.4, at
4°C overnight and paraffin embedded for morphological measurements.
The heart and the rest of the thoracic aorta were then immediately
frozen in liquid nitrogen and processed for RNA extraction for Northern
blot analysis.
Morphological Analysis
Tissue sections (5 µm thick) were cut and mounted on
Superfrost-plus slides (Fisher Scientific). After deparaffinization
with xylene and rehydration with graded ethanol, each section was
stained with hematoxylin and eosin. The computerized
image-analysis system used in the present experiments was
Bioscan Optimas software run on a 33-MHz 80486 IBM PC–compatible
computer with an Imaging Technology Vision Plus-AT CFG digitalizing
card. The inputs for this system included a Nikon Optiphot microscope
with a Hitachi HV-C10 charge-coupled device (CCD) color video camera.
The outputs from the imaging card were displayed on a 19-inch
high-resolution Sony color video monitor. The image-analysis
system was calibrated before each section was read so light level and
camera sensitivity were consistent for all measurements. The
luminal diameter was calculated from the inner circumference. The
medial-intimal area was measured in six sections from each vessel.
Vessels that were not sectioned transversely or that showed any
indication of compression were not used.1 6
cDNA Probe
A 0.8-kb fragment (-180 to +610) from the coding region of rat
AT1A cDNA (a generous gift from Dr Tadashi Inagami,
Vanderbilt University, Nashville, Tenn)13 was used as a
template to make AT1 probes. Each probe was labeled with
[32P]dCTP (Amersham Co) using a random primer DNA
labeling system (Amersham), and unincorporated nucleotides
were separated using a G-50 spin column (Worthington Biochemical
Corp).
Northern Blots
Total heart and thoracic aorta RNA were extracted by the
guanidinium thiocyanate/phenol/chloroform extraction
protocol.14 Electrophoresis of 20 to 30 µg denatured RNA
was carried out in a 1% agarose gel containing 2.2 mol/L formaldehyde.
RNA was transferred to a positively charged nylon membrane (Fisher Co),
and the blot was prehybridized for 5 hours at 42°C in hybridization
buffer (50% deionized formamide, 5x Denhardt's solution, 5x SSC,
0.5% sodium dodecyl sulfate, and 200 µg/mL denatured salmon
sperm DNA) and then hybridized with the 32P-labeled probes
for 18 to 20 hours at 42°C. At the end of this period, the blot was
washed successively in 2x, 1x, and 0.5x SSC containing 0.1% sodium
dodecyl sulfate at 60°C. After exposure to x-ray film,
autoradiographic signals were scanned with a laser
densitometer (Ultrascan XL, Pharmacia). To control the differences in
RNA loading, blots were incubated at 90°C for 10 minutes in 20
mmol/L Tris-HCl (pH 8.0) to strip off the cDNA probes and then were
rehybridized with 32P-labeled GAPDH cDNA probes.
AT1 mRNA levels were expressed as ratios to GAPDH mRNA.
Statistical Analysis
All values are expressed as mean±SEM, and "n"
represents the number of rats. Differences between groups were
determined by ANOVA followed by the Tukey-Kramer multiple comparison
test. Differences were considered statistically significant at a value
of P<.05.
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Results |
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Baseline body weight was not significantly different among the three rat groups (sham, 339±5 g; RRM, 347±7 g; RRM+Cap, 337±5 g). In sham-operated rats, body weight increased significantly over the experimental period (392±3 g, P<.05). In contrast, in all rats subjected to RRM (337±21 g) or RRM+Cap (317±13 g), body weight did not significantly change compared with baseline. Thus, at the end of the study, body weight was significantly greater in the sham-operated than in both the RRM and RRM+Cap groups.
Beginning at day 6 after surgery and continuing for the rest of the
study period, tail-cuff systolic BP was significantly higher in
the RRM rats than in the sham-operated group (Fig 1
).
The increase in BP in the RRM+Cap group did not become significant
until day 9 after surgery compared with the sham-operated group. BP in
the RRM+Cap group was not significantly different from that of the RRM
group during the entire experimental period.
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Mean arterial pressure responses to bolus injections of Ang
I (150 ng/kg) and Ang II (150 ng/kg) were measured in all three rat
groups to evaluate the efficacy of ACE inhibition by captopril. In
RRM+Cap rats, the pressor response to Ang I was abolished, whereas the
pressor response to Ang II remained unmodified compared with responses
in sham-operated and RRM rats (Fig 2), suggesting that
captopril effectively inhibited ACE activity.
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The diameter of the aortic lumen was significantly larger in RRM (1.733±0.044 mm) and RRM+Cap (1.689±0.021) rats compared with sham-operated rats (1.575±0.008, P<.05). Likewise, the medial-intimal area of the aorta was significantly greater in RRM (6.667±0.331x105 µm) and RRM+Cap (6.012±0.175) rats compared with sham-operated rats (5.120±0.040, P<.05), indicating that hypertrophy of the aortic wall occurred in RRM rats with or without captopril treatment.
Heart weight–to–body weight ratio was significantly higher in RRM (0.349±0.013 g/100 g body wt) and RRM+Cap (0.361±0.020) rats compared with sham-operated rats (0.260±0.001, P<.05), indicating that hypertrophy of the heart occurred in these rats and ACE inhibition by captopril at this specific dose and time period did not prevent the hypertrophy of the heart induced by RRM.
AT1 mRNA levels in the aorta were determined by Northern
blot analysis in all three experimental groups (Fig 3A). Blots were then stripped and rehybridized to GAPDH
mRNA probes. Densitometric analysis indicated that the ratio of
AT1 to GAPDH mRNA was significantly increased in the RRM
compared with sham-operated rats (Fig 3B). Captopril prevented the
increase in the AT1-GAPDH mRNA ratio induced by RRM.
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Northern blot analysis of AT1 mRNA levels in the
heart in each of the three groups is shown in Fig 4A.
Blots were then stripped and rehybridized to GAPDH mRNA probes.
Densitometric analysis indicated that the ratio of
AT1 to GAPDH mRNA was significantly increased in the RRM
compared with sham-operated rats (Fig 4B). Captopril did not prevent
the increase in AT1-GAPDH mRNA ratio induced by RRM.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although a local tissue RAS has been suggested to play an important role in the cardiac and vascular hypertrophy in RRM hypertensive rats, regulation of the gene encoding the Ang II receptor in these tissues remains unknown. We therefore designed the present experiments to test the hypothesis that RRM hypertension upregulates gene expression of the AT1 receptor in the thoracic aorta and heart through an Ang II–dependent mechanism. The major new finding of these studies is that RRM hypertension significantly upregulates AT1 gene expression in both hypertrophied aorta and heart. In addition, the increase in AT1 mRNA levels can be prevented in the aorta but not in the heart by ACE inhibition with captopril treatment administered at a nondepressor dose. This indicates that different mechanisms mediate the regulation of AT1 gene expression in these tissues.
It is well known that ACE inhibitors prevent the development of hypertension and inhibit cardiac hypertrophy in RRM hypertensive rats.3 4 However, it also has been shown that the BP-lowering effect and prevention of cardiac hypertrophy in RRM rats depend on the dose and type of ACE inhibitor used.4 12 Because one of the purposes of the present study was to define the role of Ang II, independent of BP, on AT1 mRNA expression in the aorta and heart of RRM hypertensive rats, it was our intention to choose a captopril dose that does not decrease BP in RRM hypertensive rats but effectively inhibits ACE activity as demonstrated by preventing the BP rise in response to exogenously injected Ang I.12 Indeed, the present study confirmed previous findings that whereas ramipril prevents the development of hypertension,12 30 mg/kg per day captopril does not decrease BP in RRM rats but abolishes the pressor response to Ang I injection.
Although 30 mg/kg per day captopril did not prevent cardiac hypertrophy in the present study, chronic inhibition of Ang II production with the ACE inhibitor perindopril has been shown to prevent cardiac hypertrophy induced by RRM hypertension.4 This cardioprotective effect was not pressure dependent because perindopril did not lower the BP.4 These observations suggest that Ang II activity, which plays an important role in the abnormal growth of the heart in this model, may be functionally enhanced in the heart of RRM rats and that captopril and perindopril may have different degrees of penetration into the cardiac tissue, resulting in different cardioprotective effects. The circulating RAS is suppressed in RRM rats.4 Therefore, potential explanations for the cardioprotective effect of perindopril include an increase in the local synthesis of RAS components, an increase in the affinity of the binding of Ang II to its receptor, and an increase in Ang II receptor number or receptor gene expression. However, it has been demonstrated that local synthesis of RAS components in the heart is not increased in RRM rats because cardiac tissue Ang II levels are decreased in cases of RRM hypertension.4 We therefore examined AT1 mRNA levels in the heart and found that RRM hypertension was associated with significantly increased AT1 gene expression. Similarly, RRM hypertension also upregulated AT1 mRNA expression in the aorta.
Mechanisms by which AT1 gene expression could be upregulated in the heart and aorta in RRM hypertension are unknown. It has been demonstrated that low sodium intake decreases the number of Ang II receptors in the mesenteric arteries.15 Therefore, the high salt intake of RRM rats could have had a stimulatory effect on AT1 gene expression in the heart and aorta. However, this possibility seems unlikely because the sham-operated rats were also fed high salt. It has been shown that AT1 receptor mRNA and density in the heart are significantly increased in spontaneously hypertensive and two-kidney, one clip hypertensive rats.16 Therefore, BP elevation could have upregulated AT1 mRNA in the heart and aorta of RRM hypertensive rats. Indeed, in the heart, upregulation of AT1 mRNA appears to be pressure dependent because normalization of BP with the AT1 receptor antagonist completely reversed the increase in receptor message and density in renin-dependent or -independent hypertensive models.16 However, in the aorta, a pressure-dependent mechanism seems unlikely because captopril treatment prevented the RRM-induced increase in aortic AT1 mRNA levels despite unchanged BP levels. Our data suggest that AT1 mRNA expression in the aorta is regulated at least in part by Ang II, kinin, or prostaglandin levels in RRM hypertension. However, it seems unlikely that decreased circulating and/or local Ang II levels are responsible for the upregulation of AT1 gene expression in the aorta of RRM rats because inhibition of Ang II production with captopril prevents the increase in AT1 gene expression in these rats. Therefore, it is possible that RRM hypertension decreases kinin or prostaglandin production in the aorta, which accounts for the upregulation of aortic AT1 gene expression in these rats. This speculation is based on the fact that captopril treatment, known to cause accumulation of kinins and prostaglandins, blocks the increase in aortic AT1 gene expression in this model. A cautionary note: Because of the short elimination half-life (1.7 hours) of captopril, we cannot rule out the possibility that the difference in tissue blockade between aortic and myocardial ACE may account for the different regulatory mechanism of AT1 gene in the present study.
Although dissociation between gene expression and protein products is possible, it is more likely that increased AT1 mRNA levels result in an increase in receptor protein synthesis. If this speculation is correct, increased Ang II receptor number may contribute to the functional and structural changes of the heart and aorta observed in RRM rats even when circulating Ang II concentrations are low. We and others have previously demonstrated that ACE inhibitors attenuate cardiac and vascular hypertrophy to a degree far greater than would be expected from their effect on systemic BP.1 2 3 4 The growth-inhibitory effect of ACE inhibition may result from the inhibition of the RAS or accumulation of bradykinin or prostaglandins.1 17 18 19 In the present experiment, however, a nondepressor dose of captopril did not prevent hypertrophy of the heart and aorta. It is possible that higher doses and a longer treatment period of captopril may prevent the abnormal growth of the heart and aorta because we have previously shown that captopril treatment at 100 mg/kg per day for 4 weeks, which also does not alter BP, prevents aortic hypertrophy in one-kidney, one clip hypertensive rats, which is also a renin-independent model.1
In conclusion, we have demonstrated that RRM hypertension significantly increases AT1 gene expression in both the heart and aorta. These gene responses are mediated by different mechanisms in these tissues. Our data suggest that in aorta, an Ang II– or kinin-dependent mechanism is operant, which is in contrast to an Ang II–or kinin-independent mechanism in the heart. Thus, RRM-induced upregulation of AT1 mRNA in the heart may be pressure dependent. We propose that the existence of distinct regulatory mechanisms will provide an opportunity for selective manipulation of Ang II receptors in different tissues. This could provide a means for differentially altering BP or tissue growth in cardiovascular disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health grant HL-52279 and a grant from The Upjohn Co to Dr Donna H. Wang. Dr Donald J. DiPette is a recipient of an Established Investigator Award from the American Heart Association. We thank Dr Tadashi Inagami for providing AT1 cDNA. We also thank Bristol-Myers Squibb Co for providing captopril. We acknowledge Wilma Frye for her expert secretarial skills.
Received January 11, 1996; first decision March 6, 1996; accepted April 26, 1996.
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References |
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