Vezf1 regulates cardiac structure and contractile function

Abstract

Background: Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart. Methods: The role of Vezf1 in regulating cardiac growth and contractile function was studied in zebrafish and in primary cardiomyocytes. Findings: We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts. Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to b-adrenergic stimuli. However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca 2+ transient kinetics. Gene ontology enrichment analysis indicates that Vezf1 regulates cardiac muscle contraction and dilated cardiomyopathy related genes and we identify cardiomyocyte Myh7/b-MHC as key target for Vezf1. We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1. Interpretation: We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease.

Zebrafish Heart Failure Models

“…In adult zebrafish, we found fractional volume shortening to be the most reliable method (Narumanchi et al, 2019). From the same fast frame-rate recordings, cardiac relaxation time may be measured (Paavola et al, 2020). In embryonic zebrafish, stroke volume may also be quantified with measurement of erythrocyte flow velocity in the aorta (Paavola et al, 2013).…”

“…Increased edema is associated with HF. Pericardial edema is easy to quantify in embryonic zebrafish (Paavola et al, 2020), however on its own it is a very non-specific finding. To our knowledge, pericardial or peripheral edema remain largely unquantified in adult zebrafish.…”

“…Ventricles marked with arrows and atria marked with arrowheads. Adapted with permission from Paavola et al (2020) .…”

“…In adult zebrafish, we found fractional volume shortening to be the most reliable method ( Narumanchi et al, 2019 ). From the same fast frame-rate recordings, cardiac relaxation time may be measured ( Paavola et al, 2020 ).…”

“…Vascular endothelial zinc finger 1 ( vezf1 ) is a transcription factor regulating vasculogenesis and angiogenesis. Expression of vezf1 is decreased in diseased human and murine myocardium ( Paavola et al, 2020 ). Knockdown of vezf1 with morpholinos in zebrafish embryos impairs cardiac growth and contractile response to beta-adrenergic stimuli suggesting a role for vezf1 in cardiac remodeling ( Paavola et al, 2020 ).…”