A positive feedback loop contributes to the deleterious effects of angiotensin.

W hen a basic scientist looks at heart failure, he sees a disease that appears to originate from any damage that causes low cardiac output, is progressive, and elicits a variety of physiological responses that attempt to correct the depressed cardiac function. Furthermore, these reflex physiological responses to low cardiac output—increased sympathoadrenal tone, increased activity of the renin–angiotensin system and other systems that maintain blood pressure, left ventricular remodeling, and cardiac hypertrophy—seem deleterious, because the pump is overworked and failing and cannot be expected, in the long run, to respond well to increased load or increased inotropic stimulation. The disease looks like a downward spiral, a spiral that therapy must interrupt. Models of heart failure have provided rationales for therapy and experimentation. A cardio-renal model viewed heart failure as a problem of salt and water retention originating with alterations in renal blood flow; a cardio-circulatory, or hemodynamic, model ascribed heart failure to vasoconstriction and reduced pumping capacity of the heart. These models provided rationales for the use of diuretics, vasodilators, and inotropic agents as therapies but mechanistically did not account for the progressive worsening of the disease or the fact that inotropic interventions produce improvements in cardiac contractility but do not slow the progression of the disease or reduce mortality. More recently, attention has focused on some of the neural paracrine autocrine mechanisms that constitute the reflex responses to low output and on the importance of signaling pathways regulating cell growth, apoptosis, and cell survival (1–3). Mann and Bristow (4) have suggested a synthesis, the biomechanical model, that emphasizes that the components of altered cardiac function and cardiac remodeling interact, such that one will invariably cause the other, and both will be sustained by neurohumoral responses. Among the humoral factors involved, much attention has been focused on the renin–angiotensin–aldosterone axis and on therapies that lower the levels of renin [ -adrenergic antagonists, some of which may also cause vasodilation via 3 receptor activation of NO production (5)], that reduce levels of angiotensin II (Ang II) [angiotensin-converting enzyme (ACE) inhibitors], or that antagonize Ang II binding to the G protein-linked type I Ang II receptors (AT1 receptor blockers) (6). These drugs inhibit the immediate, intermediate, and long-term effects of Ang II, reducing the pressure against which the heart pumps, slowing the progression of remodeling, and reducing mortality caused by heart failure (Fig. 1). ACE inhibitors and AT1 antagonists have also been useful in demonstrating that Ang II is a growth and apoptotic factor (6, 7). Myocyte apoptosis has been demonstrated in late-stage human heart failure and may constitute an important and progressive component of the disease. The article by Ding et al. (8) in this issue of PNAS suggests a putative molecular mechanism that may contribute to myocyte apoptosis in response to Ang II. Angiotensin activates a great variety of signaling pathways (6). Via the AT1 receptor, Ang II activates three G proteins (Gi, Gq, and G12/13) that couple to the activation of a plethora of protein kinase cascades, causing immediate responses and longer-term responses that occur via transcriptional regulation. An apoptotic response to angiotensin has been reported (2, 4, 7), but neither the mechanism nor the involvement of specific signaling pathways is clear, although the participation of p38 mitogen-activated protein kinase, NFAT3, and reactive oxygen species has been proposed. The Gq–PLC–Ca –PKC pathway is implicated in the cardiovascular effects of Ang II. Moderate overexpression of G q (or of PKC isoforms) causes hypertrophy and cardiac dysfunction (9–11); high levels of G q activity cause heart failure. Gq activity has been inhibited in transgenic mice by overexpression of the carboxyl-terminal peptide of G q; inhibitor-expressing transgenic mice have a reduced hypertrophic response to aortic constriction (12), demonstrating that Gq activation is necessary for this hypertrophic response. Overexpression and knockout of the AT1 receptor produce phenotypes that are consistent with the Gq data (13, 14). What Ding et al. (8) have found builds on previous work from their laboratory. They have reported that a cyclic nucleotide phosphodieserase, PDE3A, is downregulated in tissue taken from failing