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.
- MeSH
- dánio pruhované MeSH
- embryo nesavčí MeSH
- endoteliální buňky pupečníkové žíly (lidské) cytologie enzymologie MeSH
- fyziologická neovaskularizace genetika MeSH
- genetické lokusy MeSH
- genom * MeSH
- HEK293 buňky MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- malá interferující RNA genetika metabolismus MeSH
- mapování chromozomů MeSH
- mitochondrie genetika metabolismus MeSH
- myokard cytologie enzymologie MeSH
- savčí chromozomy chemie MeSH
- sekvence aminokyselin MeSH
- sekvenční homologie aminokyselin MeSH
- sekvenční seřazení MeSH
- signální transdukce MeSH
- tryptofan-tRNA-ligasa antagonisté a inhibitory genetika metabolismus MeSH
- vývojová regulace genové exprese * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
