Abstract 57: First Induced Heart Failure Model in Adult Zebrafish by Chronic Isoproterenol Treatment

Abstract

Impaired β-adrenergic signal transduction is a common molecular alteration found in heart failure (HF). Chronic catecholamine release and overstimulation of β-adrenergic receptors (β-ARs) in the failing heart results in their desensitization, largely mediated through upregulation of the G-protein coupled receptor kinase 2 (GRK2), and consequently to the progression into HF. Chronic activation of β-ARs by isoproterenol (iso) infusion efficiently induces HF in mice, while therapeutic targeting of GRK2 in HF animal models preserves cardiac function, highlighting their significance in HF progression. Zebrafish represents an established model to evaluate genetic causes of HF and to screen for novel therapeutic targets. However, the contribution of the β-A system in zebrafish models of HF is not known. We here systematically analyzed the effect of iso on heart function in larval and adult zebrafish. Larvae first responded to iso with 3 days of age (d). Here, β-AR stimulation resulted in the activation of conserved signaling components and in the induction of common stress responsive genes. Chronic β-AR stimulation for 5 days induced signs of HF accompanied by similar expression changes seen in mammals. As heart phenotypes are usually not analyzed in larval zebrafish beyond 3d, our data implicates that previous studies neglected a possible impact of β-AR signaling, particularly important when screening for therapeutic components. Adult zebrafish recently emerged as an attractive cardiac model, especially for regenerative medicine. Echocardiography revealed that in adult zebrafish hearts, iso robustly enhanced cardiac function. Chronic β-AR stimulation for 14 days efficiently induced HF symptoms. Consistent with mammals, we found reduced expression of β-ARs and elevated expression of GRK2 and ANP. Additionally, these fish develop essential characteristics accompanied with HF, including increased cell death and elevated inflammation. In conclusion, we show that β-AR function in zebrafish is comparable to that in mammals. Further, we present the first iso-induced HF model in adult zebrafish, thereby introducing adult zebrafish as a particularly valuable model to study the pathogenesis of HF and to test for novel therapeutic strategies to treat HF.