title: Wars2 is a determinant of angiogenesis.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore.
authors.forename: Mao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Patrick
authors.identifier: 0000-0001-9241-5980
authors.initials: P
authors.lastname: Sips
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Ester
authors.initials: E
authors.lastname: Khin
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
authors.forename: Ximing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Anissa Anindya
authors.initials: AA
authors.lastname: Widjaja
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.|National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Permeen
authors.initials: P
authors.lastname: Yusoff
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Pervinder Kaur
authors.initials: PK
authors.lastname: Choksi
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Nicole Shi Jie
authors.initials: NS
authors.lastname: Ko
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.|National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Epstein
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Institute of Physiology, Czech Academy of Sciences., 142 20 Prague 4, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Houštěk
authors.affiliation: Institute of Physiology, Czech Academy of Sciences., 142 20 Prague 4, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Mracek
authors.affiliation: Institute of Physiology, Czech Academy of Sciences., 142 20 Prague 4, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Nuskova
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Mikell
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Jessie
authors.initials: J
authors.lastname: Tan
authors.affiliation: National Heart and Lung Institute, Royal Brompton Campus, Imperial College London, London SW3 6NP, UK.
authors.forename: Francesco
authors.identifier: 0000-0002-2882-4226
authors.initials: F
authors.lastname: Pesce
authors.affiliation: Institute of Physiology, Czech Academy of Sciences., 142 20 Prague 4, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Kolar
authors.affiliation: Department of mathematics, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
authors.forename: Leonardo
authors.identifier: 0000-0002-6381-2327
authors.initials: L
authors.lastname: Bottolo
authors.affiliation: Department of Radiological, Oncological and Anatomo-Pathological Sciences, University of Rome, 00161 Sapienza, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany.|Charité-Universitätsmedizin, 10117 Berlin, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 13125 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: Institute of Physiology, Czech Academy of Sciences., 142 20 Prague 4, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Calum
authors.initials: C
authors.lastname: MacRae
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, 8 College Road, Singapore 169857, Singapore.|National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.|National Heart and Lung Institute, Royal Brompton Campus, Imperial College London, London SW3 6NP, UK.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000737:chemistry; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D016678:Genome; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014369:Tryptophan-tRNA Ligase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D034741:RNA, Small Interfering; D014369:Tryptophan-tRNA Ligase