RESUMEN

Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases.

Asunto(s)

Regulación del Desarrollo de la Expresión Génica , Genoma , Células Endoteliales de la Vena Umbilical Humana/enzimología , Mitocondrias/genética , Neovascularización Fisiológica/genética , Triptófano-ARNt Ligasa/genética , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Cromosomas de los Mamíferos/química , Embrión no Mamífero , Sitios Genéticos , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Mitocondrias/metabolismo , Miocardio/citología , Miocardio/enzimología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transducción de Señal , Triptófano-ARNt Ligasa/antagonistas & inhibidores , Triptófano-ARNt Ligasa/metabolismo , Pez Cebra