Enhanced Angiotensin II Activity in Heart Failure

Abstract

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.(Circ Res. 2001;88:654-658.)

Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis

“…In vitro and in vivo studies have demonstrated that Ang II induces cardiomyocyte apoptosis primarily via the type 1 (AT1) receptor 32 ; however, the mechanisms by which Ang II induced cardiomyocyte apoptosis remain largely unknown. Regardless of the effect of Ang II treatment on cAMP levels, we demonstrated that AT1R stimulation leads to PDE3A reduction, CREB activation, ICER induction, and cardiomyocyte apoptosis similar to ␤-AR stimulation with isoproterenol.…”

Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart

“…22,23 Previously, in vitro studies have shown that AT 2 -R stimulation inhibits the growth of various cell types, including cardiomyocytes, 9 by counteracting AT 1 -R signaling. However, in 2 different lines of AT 2 -R knockout mice, either pressure overload failed to generate LVH 11,24 or the increases in ventricular mass and myocyte cross-sectional area were comparable to those in nontransgenic littermates.…”

Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?

“…9,10 However, the finding that activation of AT 2 may, in some tissues, result in parallel rather than opposite effects to AT 1 activation (see below) suggests that AT 1 and AT 2 may share, at least in part, some common signaling pathways.…”