title: Enhanced angiotensin II activity in heart failure: reevaluation of the counterregulatory hypothesis of receptor subtypes.
abstract: There are strong data favoring the pathogenic role of angiotensin II type 1 receptor (AT(1)) 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 (AT(2)) may counterregulate AT(1) receptor effects during cardiac development and during the evolution of cardiac hypertrophy and heart failure. In this review, we examine the potential role of AT(2) 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 AT(2) receptor do not suggest that AT(2) signaling is essential for cardiac development. Moreover, the proposed antigrowth effects of AT(2) receptor signaling in pathological cardiac hypertrophy could not be shown in two mice models both deficient in AT(2) receptors. The role of AT(2) 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 AT(2) 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 AT(2) receptor in the failing myocardium. In this review, we conclude that the collective evidence does not strongly support a net beneficial effect of AT(2) stimulation in the diseased myocardium.
authors: Hatter Institute and Medical Research Council Inter-University Cape Heart Group, University of Cape Town Medical School, Cape Town, South Africa. Opie@Capeheart.uct.ac.za
authors: L H
authors: LH
authors: Opie
authors: M N
authors: MN
authors: Sack
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II