Natriuretic peptide receptors and atrial-selective fibrosis: potential role in atrial fibrillation

This editorial refers to ‘Absence of natriuretic peptide clearance receptor attenuates TGF-β1-induced selective atrial fibrosis and atrial fibrillation’ by D. Rahmutula et al., pp. 357–372. Atrial fibrillation (AF) is a significant cause of population morbidity, mortality, and preventable stroke.1 Underlying mechanisms are under active investigation, with a view to better understand pathophysiology and thereby improve therapeutic options.2 Cardiac fibrosis plays an important role in the occurrence of AF3 and its response to therapy.4 The atria appear to be particularly prone to fibrosis.3 For example, in dogs with cardiac remodelling due to tachycardiomyopathic heart failure (HF), atrial fibrous-tissue content increases much more than ventricular, reaching over 20-fold the ventricular level, accompanied by enhanced phosphorylation of mitogen-activated protein kinases and transforming growth factor-β (TGF-β) in atria.5 Transgenic mice engineered to overexpress constitutively active TGF-β show prominent atrial-selective fibrosis and AF susceptibility, despite similar transgene-expression in both atria and ventricles.6 The basis for the particular atrial susceptibility to fibrosis is poorly understood and might provide clues to novel fibrosis-prevention interventions of value in managing AF. Consistent with in vivo remodelling data, atrial fibroblasts (AFBs) are more susceptible than ventricular (VFBs) to stimulation by a variety of profibrotic interventions.7,In vitro studies suggest that platelet-derived growth factor (PDGF) differences might contribute to differential AFB-VFB responses,7 consistent with recent findings showing an important in vivo contribution of signalling downstream to PDGF in AF-promoting atrial fibrosis.8 Work on human tissues and TGF-β-overexpressing mice by Rahmutula et al.9 pointed to a primary role of TGF-β receptor binding or phosphorylation in differential atrial fibrosis. Atrial natriuretic peptide (ANP) is produced primarily in the atria from a larger precursor, principally via a convertase known as corin.10 ANP has a prominent natriuretic–diuretic action on the kidneys, along with anti-cardiac hypertrophic and antihypertensive actions. Accordingly, corin-deficiency causes hypertension and heart disease. ANP is cleared by binding to the natriuretic peptide receptor (NPR) type-C (NPR-C), followed by internalization and lysosomal degradation, as well as by neprilysin-induced breakdown. Some of the beneficial effects of dual angiotensin-neprilysin inhibition by sacubitril in HF might be due to reduced breakdown/accumulation of ANP. Prior work has linked ANP-dysregulation to AF, with enhanced atrial deposition of ANP-containing amyloid-protein being closely linked to age-related AF-occurrence.11 In addition, a gain-of-function ANP gene mutation is implicated in familial AF.12 In this issue of Cardiovascular Research, of Rahmutula et al.13 present an interesting and elegant series of studies exploiting transgenic mouse models to examine the potential interactions between NPRs and TGF-β in atrial-selective fibrosis and AF development. They studied the effect of NPR-C knockout in two profibrotic mouse models, TGF-β-overactivation and transverse aortic constriction. In both of the models, NRP-C knockout suppressed atrial fibrosis and AF-inducibility increases, whereas NPR-C knockout alone appeared to have no significant effect on fibrous-tissue content. In vitro studies indicated that NPR-C knockout increases NPR-A signalling in TGF-β-overexpressing AFBs, and also reduces collagen-1 gene and protein expression. The authors hypothesized that enhanced ANP-signalling through NPR-A due to reduced ANP-clearance might be responsible for the antifibrotic effects of NRP-C knockout (Figure 1). To test this notion, the authors simultaneously knocked down NRP-C and NRP-A in AFBs. NRP-A knockdown eliminated the ability of NRP-C knockdown to suppress TGF-β signalling and collagen-production, consistent with the notion that the beneficial effects of NRP-C suppression require intact ANP-induced signalling through NPR-A. Hypothesized mechanisms underlying observations of Rahmutula et al. Natriuretic peptides like atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP) interact with natriuretic peptide receptors (NPRs) type A (NPR-A) and C (NPR-C) in the cell membrane (sarcolemma). Both NPRs have an extracellular domain (ECD); NPR-A also has a kinase homology domain (KHD) and a guanylyl cyclase domain (GCD). The GCD catalyses the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which has antifibrotic actions. NPR-C is predominantly a clearance receptor, which internalizes natriuretic peptides and allows for their breakdown in lysosomes. (A) The observations of Rahmutula et al. in transgenic (TG) mice overexpressing constitutively active transforming growth factor (TGF)-beta or mice subjected to transverse aortic constriction (TAC) to cause cardiac remodelling. These mice develop atrial fibrosis and susceptibility to atrial fibrillation (AF). (B) The observations when mice with NPR-C knockout (KO) are crossed with TGF-beta TG mice or are subjected to TAC. Because these mice lack NPR-C, there is less clearance of natriuretic peptides, allowing more peptide to be available to interact with NPR-A; enhanced NPR-A signaling increases cGMP production and attenuates the development of atrial fibrosis and AF susceptibility. The identification of the mechanisms underlying atrial-selective fibrosis has the potential to reveal new molecular targets for anti-AF therapy, which might complement catheter-based techniques to target the consequences of atrial fibrosis by forestalling the emergence of new fibrosis-related AF-drivers after ablation.14 There is persuasive evidence for a role of ANP in AF,11–13 and an improved understanding of the role of ANP and the various NPRs in atrial profibrillatory remodelling would clearly be of value. The study by Rahmutula et al.13 is a useful step in this direction, pointing to molecular cross-talk between ANP and TGF-β in atrial fibrosis and pathogenesis, as well as differential contributions of various NPRs to the action and clearance of ANP. The work does have some limitations. Most importantly, the findings are somewhat contradictory to those of previously published work in the literature. Egom et al.15 studied sinus node and atrial properties in NPR-C knockout mice, and observed increased atrial fibrous-tissue content, slowed atrial conduction and AF-promotion as a result of the elimination of NPR-C. Unlike Rahmutula et al., they did not examine the effects of NPR-C knockout on the consequences of AF-promoting pathology. Had they done so, they might also have noted protection from NPR-C suppression in a profibrotic context. Nevertheless, their results clearly differ from those of Rahmutula et al.,13 in that the latter group found no evidence of changes in atrial fibrosis or arrhythmia susceptibility in mice lacking NPR-C function in the absence of AF-promoting interventions. This area is clearly complex and much more work needs to be done in order to understand the contributions of natriuretic peptides and their receptors in cardiac remodelling, particularly in relation to AF. Conflict of interest: none declared. The Canadian Institutes of Health Research (Foundation Grant 148401) and the Heart and Stroke Foundation of Canada (G-16-00012708).