Activation of ErbB4 attenuates atrial fibrillation in mice
Atrial fibrillation (AF), the most common arrhythmia, results from electrical and structural remodeling of the atria. Current therapies focus on symptomatic treatment and do not target the structural problem. This implies a high medical need for new AF therapies. The neuregulin-1 (NRG1)/ERBB system plays a compensatory role during heart failure by acting on cardiomyocytes and mitigates fibrosis in different tissues, including the myocardium. In this thesis, we evaluated the effects of ERBB4 stimulation on atrial fibrosis and atrial fibrillation in a transgenic mouse model and mouse models of clinically important risk factors of AF (hypertension and obesity). Selective ERBB4 activation was induced by JK07, a recombinant fusion protein consisting of a receptor-activating fragment of human NRG1 and a human antagonistic ERBB3 immunoglobulin G1 antibody. In chapter 4, we confirmed that JK07 more selectively stimulates ERBB4. JK07 induced ERBB4/4 dimerization with similar potency but significantly higher efficacy than ERBB2/3 dimerization compared to recombinant NRG1. Moreover, we also described that JK07 reduced the upregulation of inflammatory cytokines in cultured macrophages, and the upregulation of collagen mRNA levels (type I and III) in atrial tissue samples. In chapter 5, we evaluated the effects of NRG1 and JK07 therapy in a transgenic mouse model of cardiac-specific overexpression of TNF-. Both NRG1 and JK07 did not prevent inflammatory pathways, fibrosis, and dilation of atria in these transgenic mice. Despite the early onset of severe atrial remodeling in these transgenic mice, we did not observe spontaneous AF. Next, AF inducibility -by programmed electrical stimulation- was assessed in two distinct mouse models, (chapter 6). In a first model, mice were exposed to a high concentration of angiotensin II (Ang II), and in a second model, mice received a high fat diet (HFD). We demonstrated that JK07 treatment, started upon induction of hypertension or with HFD, prevented AF inducibility and reduced the AF duration. Despite developing increased AF inducibility, these mice did not show increased atrial fibrosis. This implies that ERBB4 activation, by JK07 treatment, in mice exerts anti-AF effects through mechanisms other than anti-fibrotic effects. Moreover, when treatment with JK07 in the Ang II-induced hypertension model was given for only a brief period (one week, therapeutic regimen), similar effects on AF inducibility were observed endorsing the hypothesis. In chapter 7, we tested if JK07 has antiarrhythmic effects by acting directly on the electrical properties of atrial cardiomyocytes. This was further substantiated in experiments with conditionally immortalized atrial myocyte monolayers, showing that JK07 completely prevented inducibility of reentrant activity (spiral waves). Overall, this study identifies the ERBB4 signaling pathway as a new therapy to treat AF, targeting electrophysiological components of atrial myopathy. These observations may open new avenues to treat AF in human patients.
Antwerpen : Universiteit Antwerpen, Faculteit Farmaceutische, Biomedische en Diergeneeskundige wetenschappen, Departement Farmaceutische wetenschappen , 2024
152 p.
Supervisor: De Keulenaer, Gilles W. [Supervisor]
Supervisor: De Meyer, Guido Y. [Supervisor]
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Neuregulin-1 as a therapy for atrial fibrillation and the role of the NRG-1/ErbB4 system in atrial remodelling.
Activating the neuregulin-1/ErbB4 pathway for treatment of heart failure.
Studies of the ErbB4 receptor in myocardial non-myocytes to create new opportunities for the treatment of cardiac disease.
Development of ErbB4 Agonists for Treatment of Heart Failure.
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Publications with a UAntwerp address
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Creation 13.03.2024
Last edited 13.06.2024
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