Wars2 is a determinant of angiogenesis
- Wang, M., Sips, P., Khin, E., Rotival, M., Sun, X., Ahmed, R., Widjaja, A.A., Schafer, S., Yusoff, P., Choksi, P.K., Ko, N.S., Singh, M.K., Epstein, D., Guan, Y., Houštěk, J., Mracek, T., Nuskova, H., Mikell, B., Tan, J., Pesce, F., Kolar, F., Bottolo, L., Mancini, M., Hubner, N., Pravenec, M., Petretto, E., MacRae, C., Cook, S.A.
- Nature communications 7: 12061 (Journal)
- Registered Authors
- MacRae, Calum A.
- Angiogenesis, Cardiovascular genetics, Medical research
- MeSH Terms
- Amino Acid Sequence
- Chromosome Mapping
- Chromosomes, Mammalian/chemistry
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental*
- Genetic Loci
- HEK293 Cells
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/enzymology*
- Neovascularization, Physiologic/genetics*
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Sequence Alignment
- Sequence Homology, Amino Acid
- Signal Transduction
- Tryptophan-tRNA Ligase/antagonists & inhibitors
- Tryptophan-tRNA Ligase/genetics*
- Tryptophan-tRNA Ligase/metabolism
- 27389904 Full text @ Nat. Commun.
Wang, M., Sips, P., Khin, E., Rotival, M., Sun, X., Ahmed, R., Widjaja, A.A., Schafer, S., Yusoff, P., Choksi, P.K., Ko, N.S., Singh, M.K., Epstein, D., Guan, Y., Houštěk, J., Mracek, T., Nuskova, H., Mikell, B., Tan, J., Pesce, F., Kolar, F., Bottolo, L., Mancini, M., Hubner, N., Pravenec, M., Petretto, E., MacRae, C., Cook, S.A. (2016) Wars2 is a determinant of angiogenesis. Nature communications. 7:12061.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes