Cardiac function in zebrafish embryos is linked to an androgen receptor-adrenomedullin-proepicardium axis
Max Duong Phu1, Alessandra Guerrero Samanidis1, Sabrina Laibacher2
1Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Faculty of Medicine, Eberhard-Karls-University Tübingen, Wilhelmstrasse 56, Tübingen, 72074, Germany.
Background:
Congenital heart defects (CHDs) comprise the most common congenital malformation affecting nearly 1% of all newborns. In individuals with sex chromosome aneuploidy syndromes, however, the prevalence reaches up to 50% of all livebirths. One commonality to these syndromes is a marked reduction in sex hormones, particularly androgens. Androgen receptor (Ar) insufficiency represents a culprit in the pathophysiology of adult onset cardiovascular disease and arrhythmia, but there are no reports regarding Ar function during heart development. This is surprising as androgens along with its nuclear receptor exist already during early development, even before gonads develop and become functional.
Methods:
We evaluated the role of the Ar during vertebrate heart development by generating loss-of function in zebrafish embryos via pharmacological inhibition, transient CRISPR/Cas9 treatment, or interference of splicing as well as murine cell culture.
Results:
Attenuation of Ar function in zebrafish embryos prevents normal cardiac morphology and physiology as apparent by edema, bradycardia and arrhythmia. Molecularly, we identified increased abundance of adrenomedullin (Adm) 2a as a likely cause for the observed defects. Cellularly, these phenomena may be linked to impaired formation of proepicardial cells, which are reported to intermingle with cells of the conduction system and influence cardiac pacing.
Conclusions:
A disrupted Ar - Adm2 axis possibly contributes to the increased frequency of CHD in individuals suffering from sex chromosome aneuploidy syndrome.
