Enhanced angiotensin II activity in heart failure - Reevaluation of the counterregulatory hypothesis of receptor subtypes

There are strong data favoring the pathogenic role of angiotensin II type 1 receptor (AT(1)) activation with subsequent promotion of myocyte growth an d cardiac fibrosis in the development of cardiac hypertrophy and heart fail ure. An emerging hypothesis suggests that the activity of the angiotensin I I type 2 receptor (AT(2)) may counterregulate AT(1) receptor effects during cardiac development and during the evolution of cardiac hypertrophy and he art failure. In this review, we examine the potential role of AT(2) activit y in the context of this hypothesis. In contrast to the counterregulatory h ypothesis, studies in mice with an overabundance of, or a deficiency in, th e AT(2) receptor do not suggest that AT(2) signaling is essential for cardi ac development. Moreover, the proposed antigrowth effects of AT(2) receptor signaling in pathological cardiac hypertrophy could not be shown in two mi ce models both deficient in AT(2) receptors. The role of AT(2) receptor sig naling in cardiac fibrosis is, however, still debatable because of conflict ing data in the same two studies. In angiotensin II-evoked apoptosis in car diomyocytes, the proposed proapoptotic role of AT(2) activity could not be confirmed. Furthermore, in the progression from the bench to bedside, the r esults of two large clinical trials in heart failure, namely ELITE II and V al-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.