doi: 10.1161/hh0701.089175
© 2001 American Heart Association, Inc.
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Enhanced Angiotensin II Activity in Heart Failure
Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes
From the Hatter Institute and Medical Research Council Inter-University Cape Heart Group, University of Cape Town Medical School, Cape Town, South Africa.
Correspondence to Lionel H. Opie, MD, DPhil, Cape Heart Centre, UCT Medical School, Observatory, 7925, Cape Town, South Africa. E-mail Opie{at}Capeheart.uct.ac.za
Abstract—There are strong data favoring the pathogenic role of angiotensin II type 1 receptor (AT1) activation with subsequent promotion of myocyte growth and cardiac fibrosis in the development of cardiac hypertrophy and heart failure. An emerging hypothesis suggests that the activity of the angiotensin II type 2 receptor (AT2) may counterregulate AT1 receptor effects during cardiac development and during the evolution of cardiac hypertrophy and heart failure. In this review, we examine the potential role of AT2 activity in the context of this hypothesis. In contrast to the counterregulatory hypothesis, studies in mice with an overabundance of, or a deficiency in, the AT2 receptor do not suggest that AT2 signaling is essential for cardiac development. Moreover, the proposed antigrowth effects of AT2 receptor signaling in pathological cardiac hypertrophy could not be shown in two mice models both deficient in AT2 receptors. The role of AT2 receptor signaling in cardiac fibrosis is, however, still debatable because of conflicting data in the same two studies. In angiotensin II–evoked apoptosis in cardiomyocytes, the proposed proapoptotic role of AT2 activity could not be confirmed. Furthermore, in the progression from the bench to bedside, the results of two large clinical trials in heart failure, namely ELITE II and Val-HeFT, can be explained without ascribing a major protective role to the unopposed activity of the AT2 receptor in the failing myocardium. In this review, we conclude that the collective evidence does not strongly support a net beneficial effect of AT2 stimulation in the diseased myocardium.
Key Words: angiotensin receptor subtypes • counterregulation • renin-angiotensin system • heart failure
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