(Circulation. 1997;95:1193-1200.)
© 1997 American Heart Association, Inc.
Articles |
Selective Downregulation of the Angiotensin II AT1-Receptor Subtype in Failing Human Ventricular Myocardium
the Division of Cardiology, The Temple Hoyne Buell Heart Center Research Laboratories, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colo.
Correspondence to Michael R. Bristow, MD, PhD, Division of Cardiology, B-139, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262. E-mail bristow_m{at}defiance.hsc.colorado.edu
Background The regulation of angiotensin II receptors and the two major subtypes (AT1 and AT2) in chronically failing human ventricular myocardium has not been previously examined.
Methods and Results Angiotensin II receptors were measured by saturation binding of 125I-[Sar1,Ile8]angiotensin II in crude membranes from nonfailing (n=19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n=31) or ischemic cardiomyopathy (ISC; n=21) and membranes from a limited number of right ventricles in each category. The AT1 and AT2 fractions were determined by use of an AT1-selective antagonist, losartan. ß-Adrenergic receptors were also measured by binding of 125I-iodocyanopindolol with the ß1 and ß2 fractions determined by use of a ß1-selective antagonist, CGP20712A. AT1 but not AT2 density was significantly decreased in the combined (IDC+ISC) failing left ventricles (nonfailing: AT1 4.66±0.48, AT2 2.73±0.39; failing: AT1 3.20±0.29, AT2 2.70±0.33 fmol/mg protein; mean±SE). The decrease in AT1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73±0.40, P<.01; ISC: 3.89±0.39 fmol/mg protein, P=NS versus nonfailing). ß1 but not ß2 density was decreased in the failing left ventricles. AT1 density was correlated with ß1 density in all left ventricles (r=.43). AT1 density was also decreased in IDC right ventricles. In situ reverse transcription–polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT1 mRNA was present in both myocytes and nonmyocytes.
Conclusions AT1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of ß1 receptors. The relative lack of AT1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.
Key Words: receptors • polymerase chain reaction • angiotensin • radioisotopes
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|
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|
|
|
|
 |
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gunasegaram, R. S. Haworth, D. J. Hearse, and M. Avkiran Regulation of Sarcolemmal Na+/H+ Exchanger Activity by Angiotensin II in Adult Rat Ventricular Myocytes : Opposing Actions via AT1 Versus AT2 Receptors Circ. Res., November 12, 1999; 85(10): 919 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Bastien, A.-V. Juneau, J. Ouellette, and C. Lambert Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival Cardiovasc Res, July 1, 1999; 43(1): 77 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tanimura, V. G. Sharov, H. Shimoyama, T. Mishima, T. B. Levine, S. Goldstein, and H. N. Sabbah Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1385 - H1392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bartunek, E. O. Weinberg, M. Tajima, S. Rohrbach, and B. H. Lorell Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts Circulation, January 12, 1999; 99(1): 22 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsubara Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases Circ. Res., December 14, 1998; 83(12): 1182 - 1191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tsutsumi, H. Matsubara, N. Ohkubo, Y. Mori, Y. Nozawa, S. Murasawa, K. Kijima, K. Maruyama, H. Masaki, Y. Moriguchi, et al. Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression Circ. Res., November 16, 1998; 83(10): 1035 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Jalowy, R. Schulz, H. Dorge, M. Behrends, and G. Heusch Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1787 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Skolnick, S. E. Litwin, W. H. Barry, and K. W. Spitzer Effect of ANG II on pHi, [Ca2+]i, and contraction in rabbit ventricular myocytes from infarcted hearts Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1788 - H1797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O. Gray, C. S. Long, J. E. Kalinyak, H.-T. Li, and J. S. Karliner Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-{beta}1 and endothelin-1 from fibroblasts Cardiovasc Res, November 1, 1998; 40(2): 352 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Zisman, K. Asano, D. L. Dutcher, A. Ferdensi, A. D. Robertson, M. Jenkin, E. W. Bush, T. Bohlmeyer, M. B. Perryman, and M. R. Bristow Differential Regulation of Cardiac Angiotensin Converting Enzyme Binding Sites and AT1 Receptor Density in the Failing Human Heart Circulation, October 27, 1998; 98(17): 1735 - 1741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Zolk, M. Flesch, G. Nickenig, P. Schnabel, and M. Bohm Alteration of intracellular Ca2+-handling and receptor regulation in hypertensive cardiac hypertrophy: insights from Ren2-transgenic rats Cardiovasc Res, July 1, 1998; 39(1): 242 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.S. Krombach, M. J Clair, J. W Hendrick, W. V Houck, J. L Zellner, S. B Kribbs, S. Whitebread, R. Mukherjee, M. de Gasparo, and F. G Spinale Angiotensin converting enzyme inhibition, AT1 receptor inhibition, and combination therapy with pacing induced heart failure: effects on left ventricular performance and regional blood flow patterns Cardiovasc Res, June 1, 1998; 38(3): 631 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Senzaki, Y. A. Gluzband, P. H. Pak, M. T. Crow, J. S. Janicki, and D. A. Kass Synergistic Exacerbation of Diastolic Stiffness From Short-term Tachycardia–Induced Cardiodepression and Angiotensin II Circ. Res., March 9, 1998; 82(4): 503 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ponicke, M. Vogelsang, M. Heinroth, K. Becker, O. Zolk, M. Bohm, H.-R. Zerkowski, and O.-E. Brodde Endothelin Receptors in the Failing and Nonfailing Human Heart Circulation, March 3, 1998; 97(8): 744 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ohkubo, H. Matsubara, Y. Nozawa, Y. Mori, S. Murasawa, K. Kijima, K. Maruyama, H. Masaki, Y. Tsutumi, Y. Shibazaki, et al. Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism Circulation, December 2, 1997; 96(11): 3954 - 3962. [Abstract] [Full Text]
|
|
|
|
|
|
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|
|
|
|
|
|
G. G. N. Serneri, M. Boddi, I. Cecioni, S. Vanni, M. Coppo, M. L. Papa, B. Bandinelli, I. Bertolozzi, G. Polidori, T. Toscano, et al. Cardiac Angiotensin II Formation in the Clinical Course of Heart Failure and Its Relationship With Left Ventricular Function Circ. Res., May 11, 2001; 88(9): 961 - 968. [Abstract] [Full Text] [PDF]
|
|