© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
The renin–angiotensin system and experimental heart failure
Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany
* Corresponding author. Tel.: +49-511-532-2530; fax: +49-511-532-5412 wollert.kai{at}mh-hannover.de
Experimental studies suggest that the renin–angiotensin system (RAS) and its primary effector peptide, angiotensin II (Ang II), are involved in the pathophysiology of cardiac hypertrophy and failure. All the components required for Ang II production are present in the heart, and cardiac Ang II formation appears to be regulated independent from the circulating RAS. In animal models and in patients with heart failure, the cardiac RAS is activated and, presumably, local Ang II formation is enhanced. Several cardiac cell types express Ang II type 1 (AT1) and/or type 2 (AT2)-receptors and represent potential targets for Ang II-mediated effects. In neonatal cardiac myocytes, Ang II induces a hypertrophic response via the AT1-receptor. Likewise, activation of the AT1-receptor triggers hypertrophy in terminally differentiated cardiac myocytes and in perfused heart preparations. In the neonatal system, Ang II appears to be a major autocrine/paracrine mediator of cardiac myocyte hypertrophy in response to passive mechanical stretch. By contrast, AT1-receptor activation apparently is not required to trigger load-induced hypertrophy in the adult cardiomyocyte. Recent studies suggest that the AT2-receptor opposes AT1-receptor-mediated growth signals in neonatal and in adult cardiac myocytes. Pharmacological studies have established that a blockade of the RAS at the level of the angiotensin-converting enzyme (ACE) or the AT1-receptor ameliorates the remodeling process of the heart and prolongs long-term survival in animal models of cardiac hypertrophy and failure. The therapeutic effects of ACE inhibitors and AT1-receptor antagonists clearly suggest an important role for the ACE–Ang II–AT1-receptor axis in the development of cardiac hypertrophy and failure. It must be kept in mind, however, that these drugs enhance AT2-receptor and B2-kinin receptor-dependent signaling pathways which may contribute significantly to the beneficial effects observed in vivo. Molecular and physiological analyses of transgenic mice with a cardiac-specific overexpression of the AT1 or AT2-receptor confirm that AT1 and AT2-receptor-dependent signaling cascades potently modulate cardiac myocyte function and growth. However, studies in AT1-receptor knockout mice demonstrate that cardiac hypertrophy in response to hemodynamic overload can occur independent from the AT1-receptor. In this paper, we review recent experimental evidence suggesting a critical role for the RAS in cardiac hypertrophy and failure with special emphasis on the putative role of Ang II and Ang II-receptor signaling in cardiac myocytes.
KEYWORDS Renin–angiotensin system; Heart failure; Cardiac hypertrophy; Myocytes
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Ahmet, C. Morrell, E. G. Lakatta, and M. I. Talan Therapeutic Efficacy of a Combination of a {beta}1-Adrenoreceptor (AR) Blocker and {beta}2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a {beta}1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 178 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Schmitt, K. Fedarava, J. Falkenberg, K. Rothaus, N. K. Bodhey, C. Reischauer, S. Kozerke, B. Schnackenburg, D. Westermann, P. P. Lunkenheimer, et al. Three-dimensional alignment of the aggregated myocytes in the normal and hypertrophic murine heart J Appl Physiol, September 1, 2009; 107(3): 921 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Isidoro Tavares, P. Philip-Couderc, A. J. Baertschi, R. Lerch, and C. Montessuit Angiotensin II and tumour necrosis factor {alpha} as mediators of ATP-dependent potassium channel remodelling in post-infarction heart failure Cardiovasc Res, September 1, 2009; 83(4): 726 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Castro-Chaves, R. Fontes-Carvalho, M. Pintalhao, P. Pimentel-Nunes, and A. F. Leite-Moreira Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart Exp Physiol, June 1, 2009; 94(6): 665 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Choudhary, A. Palm-Leis, R. C. Scott III, R. S. Guleria, E. Rachut, K. M. Baker, and J. Pan All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H633 - H644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. B. Ferreira, A. V. Bacurau, F. S. Evangelista, M. A. Coelho, E. M. Oliveira, D. E. Casarini, J. E. Krieger, and P. C. Brum The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R26 - R32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Sartorio, D. Fraccarollo, P. Galuppo, M. Leutke, G. Ertl, I. Stefanon, and J. Bauersachs Mineralocorticoid Receptor Blockade Improves Vasomotor Dysfunction and Vascular Oxidative Stress Early After Myocardial Infarction Hypertension, November 1, 2007; 50(5): 919 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zheng, Y.-F. Li, I. H. Zucker, and K. P. Patel Exercise training improves renal excretory responses to acute volume expansion in rats with heart failure Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1148 - F1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimoni, D. Hunt, K. Chen, T. Emmett, and G. Kargacin Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1879 - H1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W.M. Schellings, M. Baumann, R. E.W. van Leeuwen, R. F.J.J. Duisters, S. H.P. Janssen, B. Schroen, C. J. Peutz-Kootstra, S. Heymans, and Y. M. Pinto Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats Hypertension, March 1, 2006; 47(3): 467 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Domenighetti, Q. Wang, M. Egger, S. M. Richards, T. Pedrazzini, and L. M.D. Delbridge Angiotensin II-Mediated Phenotypic Cardiomyocyte Remodeling Leads to Age-Dependent Cardiac Dysfunction and Failure Hypertension, August 1, 2005; 46(2): 426 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Aker, A. K Snabaitis, I. Konietzka, A. van de Sand, K. Bongler, M. Avkiran, G. Heusch, and R. Schulz Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits Cardiovasc Res, August 1, 2004; 63(2): 273 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Zimmerman, E. Lazartigues, R. V. Sharma, and R. L. Davisson Hypertension Caused by Angiotensin II Infusion Involves Increased Superoxide Production in the Central Nervous System Circ. Res., July 23, 2004; 95(2): 210 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Berthonneche, T. Sulpice, F. Boucher, L. Gouraud, J. de Leiris, S. E. O'Connor, J.-M. Herbert, and P. Janiak New insights into the pathological role of TNF-{alpha} in early cardiac dysfunction and subsequent heart failure after infarction in rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H340 - H350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cerbai and A. Mugelli Angiotensin AT2 receptor: the younger sibling attracts attention Cardiovasc Res, April 1, 2004; 62(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schafer, D. Fraccarollo, P. Tas, I. Schmidt, G. Ertl, and J. Bauersachs Endothelial dysfunction in congestive heart failure: ACE inhibition vs. angiotensin II antagonism Eur J Heart Fail, March 1, 2004; 6(2): 151 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Pang, R.-K. Xu, X.-B. Xu, J.-M. Cao, C. Ni, W.-L. Zhu, K. Asotra, M.-C. Chen, and C. Chen Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1063 - H1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, S. Aker, S. Belosjorow, I. Konietzka, U. Rauen, and G. Heusch Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2084 - H2090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Boateng, T. J. Hartman, N. Ahluwalia, H. Vidula, T. A. Desai, and B. Russell Inhibition of fibroblast proliferation in cardiac myocyte cultures by surface microtopography Am J Physiol Cell Physiol, July 1, 2003; 285(1): C171 - C182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schafer, D. Fraccarollo, S. K Hildemann, P. Tas, G. Ertl, and J. Bauersachs Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction Cardiovasc Res, June 1, 2003; 58(3): 655 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N C Sundgren, G D Giraud, P J S Stork, J G Maylie, and K L Thornburg Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes J. Physiol., May 1, 2003; 548(3): 881 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Verdonck, P. G.A Volders, M. A Vos, and K. R Sipido Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells Cardiovasc Res, March 15, 2003; 57(4): 1035 - 1043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gschwend, H. Buikema, R. H. Henning, Y. M. Pinto, D. de Zeeuw, and W. H. van Gilst Endothelial dysfunction and infarct-size relate to impaired EDHF response in rat experimental chronic heart failure Eur J Heart Fail, March 1, 2003; 5(2): 147 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Naito, T. Tsujino, Y. Fujioka, M. Ohyanagi, and T. Iwasaki Augmented Diurnal Variations of the Cardiac Renin-Angiotensin System in Hypertensive Rats Hypertension, December 1, 2002; 40(6): 827 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Schillinger, H. Schneider, K. Minami, R. Ferrari, and G. Hasenfuss Importance of sympathetic activation for the expression of Na+-Ca2+ exchanger in end-stage failing human myocardium Eur. Heart J., July 2, 2002; 23(14): 1118 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Bendall, A. C. Cave, C. Heymes, N. Gall, and A. M. Shah Pivotal Role of a gp91phox-Containing NADPH Oxidase in Angiotensin II-Induced Cardiac Hypertrophy in Mice Circulation, January 22, 2002; 105(3): 293 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Multani, R. S. Krombach, A. T. Goldberg, M. K. King, J. W. Hendrick, J. A. Sample, S. C. Baicu, C. Joffs, M. deGasparo, and F. G. Spinale Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2001; 6(4): 369 - 376. [Abstract] [PDF]
|
|
|
|
 |
|
 L. J Wagenaar, H. Buikema, Y. M Pinto, and W. H van Gilst Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade? Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S64 - S69. [Abstract] [PDF]
|
|
|
|
 |
|
 M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|