Atriopeptins: Protection from Myocardial Hypertrophy and Heart Failure

Discovery of a hormone-like substance in the atria of rats by de Bold et al. (1) opened a new field of research in endocrinology. Their seminal finding is that myocardium contains peptides that exert natriuretic and diuretic actions on the kidney and relax blood vessels. We now know that Professor de Bold’s “atrial natriuretic factor” consists of two different peptide hormones in a family of three different peptide agonists. Heart muscle contains atriopeptin-A and atriopeptin-B, with the first being produced primarily in the atria and the latter in ventricles (reviewed in Ref. 2). A third family member is atriopeptin-C, which is produced in many different organs and primarily exerts local or paracrine actions. All the atriopeptins exert their cellular effects via intracellular cGMP through activation of membrane guanylate cyclases (GC). The first receptor-GC protein to be identified by molecular cloning was GC-A, which selectively binds atriopeptin-A and atriopeptin-B (3). And so it goes that we once had simple endocrine loops between the heart and other organs such as the kidney, blood vessels, and adrenal gland (Fig. 1). Now the findings of Kilić et al. (4) reported in this issue clearly demonstrate that the heart has a novel and short paracrine loop, mediated by atriopeptin-A/B and their cognate receptor GC-A located on the surface of myocardial cells. Their experiments show that atriopeptins, via GC-A and intracellular cGMP, exert physiological antagonism of the myocardial actions of angiotensin, thus protecting the heart. Physiological actions of natriuretic peptides. ANP, Atriopeptin-A; BNP, atriopeptin-B. Why are these new findings important for endocrinology and medicine? One answer is the rising incidence of heart failure now that contemporary medical advances have sharply reduced the immediate mortality after myocardial infarction. Instead of dying from heart attacks, surviving patients may now face life with symptoms caused by progressive heart failure. A prominent pathophysiological feature of this disease is the progressive cardiac hypertrophy and fibrosis driven by the renin-angiotensin-aldosterone axis. Kilić et al. (4) have reproduced this pathophysiology in an animal model by implanting osmotic mini-pumps that continuously release angiotensin into transgenic mice that have no GC-A receptors on myocardial cells. Infusion of angiotensin normally elicits hypertrophy and fibrosis of the heart; responses would be greatly enhanced in angiotensin-infused mice with no myocardial GC-A. GC-A was first implicated as playing such a protective role in the myocardium when the GCA gene was globally deleted to produce GC-A-deficient animals, with GC-A knockout mice showing elevated blood pressure (5). Subsequent studies showed that GC-A knockout mice died young, apparently by heart-related maladies (6). As previously observed in humans, male GC-A knockout mice were particularly susceptible to early deaths, from heart disease associated with cardiac hypotrophy and myocardial fibrosis (7). It is difficult to interpret the findings made in global gene knockout animals, and we have learned to be skeptical of initial findings made in such models. The cardiomyocyte-specific deletion of GC-A used by Kilić et al. points clearly to the protective local role of atriopeptins and GC-A against angiotensin-driven cardiac hypertrophy and fibrosis. The findings also demonstrate that the protective effects of atriopeptins on the heart are not secondary to the blood-pressure-lowering actions of atriopeptins mediated by GC-A receptors in the vasculature. Angiotensin acts via G protein-coupled AT1 receptors to increase intracellular calcium levels, and Kilić et al. (4) demonstrate that atriopeptin antagonizes this action of angiotensin through local activation of GC-A in myocardial cells (Fig. 2). It is, however, not at all clear how elevated intracellular cGMP after stimulation of GC-A by atriopeptins may oppose the cellular actions of angiotensin leading to myocardial hypertrophy and fibrosis, because cGMP does not appear to influence the density of AT1 receptors in the heart muscle. The signal transduction mechanism postulated by Kilić et al. depicted in Fig. 2 offers novel insights into therapeutic interventions that may help to prevent cardiac hypertrophy, fibrosis, and failure, for example an orally active selective agonist of GC-A receptors to mimic the physiological effects of atriopeptin-A. To augment cGMP production via GC-A, we already have drugs to reduce metabolism of cGMP by phosphodiesterase enzymes (PDE), including the ubiquitous PDE-5 molecule. A long-acting PDE-5 inhibitor such as tadalafil might therefore be useful either alone or together with an orally active GC-A agonist and/or an angiotensin receptor blocker. In addition, the downstream signaling cascade in myocardial cells mediated by angiotensin 1 receptors may also be a novel target for pharmacological intervention to prevent heart failure. In summary, although the findings made by Kilić et al. (4) raise many new questions, their study also provides clear answers to key questions on the mechanisms whereby cardiac hormones may help protect the myocardium. Hypothesis: local ANP/GC-A signaling inhibits angiotensin II-stimulated, NHE-1/Ca2+-mediated excessive cardiac remodeling. PKG I, Protein kinase G I; NCX, Na+/Ca2+ exchanger; NHE-1, Na+/H+ exchanger type 1; Ang II, angiotensin II; CaMKII, Ca2+/calmodulin-dependent protein kinase II; pERK, phosphorylated ERK. I thank Professor Michaela Kuhn and her colleagues for providing the model illustrations used in this manuscript, which were of considerable help in my efforts to explain their findings. Guanylate cyclase phosphodiesterase enzymes.