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(Circulation. 2000;101:2678.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Regulation of Angiotensin II Receptor Subtypes During Atrial Fibrillation in Humans
From University Hospital Magdeburg, Division of Cardiology (A.G., T.S., J.C.G., H.U.K), Institute of Immunology (M.A., A.S.), Institute of Pathology (C.R.), Department of Cardiovascular Surgery (C.H.), and Institute of Experimental Internal Medicine (S.A., U.L.), Magdeburg, Germany.
Correspondence to Andreas Goette, MD, University Hospital Magdeburg, Division of Cardiology, Leipziger Str 44, 39120 Magdeburg, Germany. E-mail andreas.goette{at}medizin.uni-madgeburg.de
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Abstract |
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Background—Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT1-R and AT2-R) in patients with AF.
Methods and Results—Atrial tissue samples from 30 patients
undergoing open heart surgery were examined. Eleven patients had
chronic persistent AF (
6 months; cAF), 8 patients had paroxysmal AF
(pAF), and 11 patients were in sinus rhythm. AT1-R and
AT2-R were localized in the atrial tissue by
immunohistochemistry and quantified at the protein and mRNA level by
Western blotting and quantitative polymerase chain reaction. Both types
of AT-R were predominantly expressed in atrial myocytes in all groups.
The amount of AT1-R was reduced to 34.9% during cAF
(P<0.01) and to 51.7% during pAF
(P<0.05) compared with patients in sinus rhythm. In
contrast, AT2-R was increased during cAF (246%;
P=NS) and pAF (505%; P<0.01).
AT1-R/AT2-R mRNA content was similar in all
groups.
Conclusions—AF is associated with the down-regulation of atrial AT1-R and the up-regulation of AT2-R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.
Key Words: angiotensin • atrium • fibrillation • receptors • remodeling
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Introduction |
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Recent reports suggest that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. Pedersen et al1 provided the first evidence that angiotensin-converting enzyme (ACE) inhibitor therapy can reduce the occurrence of AF in patients with left ventricular dysfunction after myocardial infarction. In addition, Van den Berg et al2 observed that pretreatment with ACE inhibitors reduced the relapse rate of AF after electrical cardioversion. Thus, the inhibition of the cardiac angiotensin system by ACE inhibitors/angiotensin receptor antagonists might affect the pathophysiological substrate of AF and may offer a new therapeutic approach. However, the atrial expression of angiotensin II type 1 and type 2 receptors (AT1-R and AT2-R) has not been investigated in patients with AF.
The purpose of the present study was to localize atrial AT1-R/AT2-R and to quantify the expression of these receptors at the protein and mRNA level in patients with and without AF.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
After written informed consent was obtained, right atrial appendages were obtained from patients undergoing cardiac bypass surgery or mitral/aortic valve replacement. Tissue samples were taken from 11 consecutive patients with chronic, persistent AF (
6 months;
cAF) and from 11 matched patients with no history of AF (sinus rhythm
[SR]). In addition, 8 consecutive patients with documented episodes
of paroxysmal AF (pAF; 3±2 AF episodes per month) were studied
(Table
).
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Western Blotting
Tissue samples were homogenized in 2x RotiLoad
(Roth) using an UltraTurrax. Aliquots of 300 µg were separated
in 4% to 12% gradient SDS-polyacrylamide gels (Novex
Electrophoresis) and transferred onto nitrocellulose membrane BA85
(Schleicher & Schüll). Rabbit anti-AT1-R
and anti-AT2-R polyclonal antibodies (Biotrend),
goat-anti-rabbit-peroxidase (New England Biolabs), and
SuperSignal West Dura Extended Duration Substrate (Pierce) were used
for immunodetection. The resulting images were densitometrically
analyzed. The mean relative absorption units of the control
group were compared with the corresponding means of the AF groups.
Comparison of the different groups was only done on blots processed
equally and exposed on the same x-ray film.
Quantitative Polymerase Chain Reaction
One microgram of total RNA, which was prepared using
TRIZOL (Gibco BRL), was reverse-transcribed. A total of 5% of
the cDNA mixture was used for quantitative polymerase chain reaction
(PCR) by means of the Lightcycler LC24 (Idaho Technology). The 10-µL
reaction mixture consisted of 1x reaction buffer with BSA (Idaho
Technology), 3 mmol/L MgCl2, 200 µmol
of desoxyribonucleotide mixture, 0.4 U of InViTaq polymerase
(InViTec), 0.2 µL of SYBR-Green I (1:1000, Molecular Probes), and
0.5 µmol of the AT-R-specific primers
(AT1-R: 5'-GACGCACAATGCTTGTAGCCA and
5'-CTGCAATTCTACAGTCACGTATG; AT2-R:
5'-GGGCTTGTGA-ACATCTCTGG and 5'-GTAAATCAGCCACAGCGAGG).
Amounts of 18S-mRNA were used to normalize cDNA contents. Initial denaturation at 95°C for 3 s was followed by 40 cycles with denaturation at 95°C for 0 s, annealing at 65°C (AT1-R) or 60°C (AT2-R) for 3 s, and elongation at 72°C for 15 s (AT1-R) or 9 s (AT2-R). The fluorescence intensity, which reflected the amount of actually formed PCR product, was read at the end of each elongation step. Initial amounts of template mRNA were calculated by determining the time point at which the linear increase of PCR product started, relative to the corresponding points of a standard curve.
Histochemistry and Immunohistochemistry
Histochemistry and immunohistochemistry for localization of
AT-Rs were performed in a total of 15 tissue specimens (4 SR, 6 cAF, 5
pAF). Sections from formalin-fixed and paraffin-embedded specimens were
stained with hematoxylin and eosin. Immunostaining was
performed with antibodies, as specified above, directed against
AT1-R or AT2-R (dilution
1:20) following standard protocols. The specificity was controlled by
omitting the primary antibody.
Statistical Analysis
All values are expressed as mean±SD. Differences between the 3
groups of patients were evaluated using 1-way ANOVA. P<0.05
was considered statistically significant.
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Results |
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AT1-R and AT2-R
The relative amount of AT1-R in atrial tissue was significantly reduced in patients with cAF (34.9±40.9%; n=11; P<0.01) and pAF (51.7±26.6%; n=8; P<0.05) compared with patients with SR (100±58.1%; n=11). The difference between pAF and cAF was not significant (Figure
, A). The amount of
AT1-R correlated neither with AF duration nor
with left ventricular ejection fraction
(r2=0.03 and
r2=0.02, respectively;
P=NS). AT2-R was increased in patients
with pAF (505±331.6%; n=11; P<0.01) compared with
patients with SR (100±108.8%; n=11). The observed increase in
patients with cAF (246±323.2%; n=11) did not reach statistical
significance.
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P<0.05 versus SR.
B and C, Immunostaining of atrial tissue with
AT1-R antibody (red staining) in patients with SR (B) and
cAF (C). Magnification x130. D and E, Immunostaining
of atrial tissue with AT2-R antibody (red staining) in
patients with SR (D) and cAF (E). Magnification x180. AF did not
change the staining pattern in any specimen.
AT1-R and AT2-R mRNA
The amount of AT1-R mRNA was not different
in patients with cAF (85.7±80.4%; n=11) or pAF (65±36%; n=8)
compared with patients in SR (100±86.5%; n=11).
AT2-R mRNA content was not significantly
increased during cAF (179.9±156.8%; n=11) or pAF (126.2±101.4%;
n=8) compared with patients with SR (100±60.5%; n=11;
P=0.4).
Immunohistochemistry
The spatial distribution of AT-R showed no differences between
patients with and without AF. AT1-R was found in
fibroblasts, vascular smooth muscle cells, and atrial myocytes
(Figure
, B and C). AT2-R was found only in
atrial myocytes (Figure, D and E).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The action of angiotensin II is initiated by binding to AT1-R/AT2-R.3 4 Stimulation of AT1-R induces myocardial hypertrophy and the accumulation of extracellular matrix proteins; it can also affect atrial contractility.3 4 In contrast, stimulation of AT2-R inhibits proliferative processes.5
Our study describes, for the first time, the regulation of atrial AT1-R/AT2-R expression in patients with AF. pAF and cAF were associated with the down-regulation of AT1-R. An up-regulation of AT2-R was observed during pAF. In contrast, at the mRNA level, AT1-R/AT2-R expression was not significantly altered.
AF is associated with progressive structural changes of the atria, resulting in atrial dilation and loss of transport function.1 2 A previous study demonstrated that the atrial expression of ACE is increased in patients with AF, possibly leading to angiotensin II–dependent progressive atrial fibrosis.6 Increased angiotensin II tissue levels during AF may trigger the observed down-regulation of AT1-R. A reduction of AT1-R and an increase of AT2-R may, therefore, be compensatory to inhibit the progression of angiotensin II–dependent interstitial fibrosis.
The atrial expression of ACE and AT-R subtypes during AF resembles changes seen in patients with terminal left ventricular failure.3 4 6 Rogg et al3 showed that the atrial expression of AT1-R is positively correlated with left ventricular ejection fraction, whereas left ventricular ejection fraction and AT2-R are inversely related. In the present study, however, none of the patients had terminal heart failure. One can, therefore, hypothesize that the regulatory changes seen during AF characterize the presence of an "end-stage atrial myopathy." This is supported by other studies,1 2 6 which have shown the development of severe morphological/functional atrial abnormalities during cAF.
The observed changes in amounts of AT-R proteins, despite the unaltered corresponding mRNA levels, suggest that the expression of AT-R subtypes is regulated by post-transcriptional mechanisms. Underlying regulatory processes may encompass inefficient AT-R mRNA translation or decreased AT-R stability.7
In conclusion, this study shows that cAF and pAF are associated with significant changes in the atrial expression of AT1-R/AT2-R. Further studies must define possible therapeutic consequences.
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Acknowledgments |
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Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 387) and the Kultusministerium Sachsen-Anhalt (contract grant number 822A10318223). The authors thank Bianca Schultze, Karin Frank, Christine Wolf, and Ruth Hilde Hädicke for their excellent technical assistance.
Received February 17, 2000; revision received April 17, 2000; accepted April 17, 2000.
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References |
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B. J.J.M. Brundel, R. H. Henning, H. H. Kampinga, I. C. Van Gelder, and H. J.G.M. Crijns Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 315 - 324. [Abstract] [Full Text] [PDF]
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S. Nattel Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res, May 1, 2002; 54(2): 347 - 360. [Abstract] [Full Text] [PDF]
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B. J.J.M Brundel, J. Ausma, I. C van Gelder, J. J.L Van Der Want, W. H van Gilst, H. J.G.M Crijns, and R. H Henning Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 380 - 389. [Abstract] [Full Text] [PDF]
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K. Shinagawa, H. Mitamura, S. Ogawa, and S. Nattel Effects of inhibiting Na+/H+-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling Cardiovasc Res, May 1, 2002; 54(2): 438 - 446. [Abstract] [Full Text] [PDF]
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Y. Shi, D. Li, J.-C. Tardif, and S. Nattel Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure Cardiovasc Res, May 1, 2002; 54(2): 456 - 461. [Abstract] [Full Text] [PDF]
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D. Li, K. Shinagawa, L. Pang, T. K. Leung, S. Cardin, Z. Wang, and S. Nattel Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing-Induced Congestive Heart Failure Circulation, November 20, 2001; 104(21): 2608 - 2614. [Abstract] [Full Text] [PDF]
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M. Arndt, U. Lendeckel, C. Rocken, K. Nepple, C. Wolke, A. Spiess, C. Huth, S. Ansorge, H. U. Klein, and A. Goette Altered Expression of ADAMs (A Disintegrin And Metalloproteinase) in Fibrillating Human Atria Circulation, February 12, 2002; 105(6): 720 - 725. [Abstract] [Full Text] [PDF]
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