Wars2 is a determinant of angiogenesis

Mao Wang, Patrick Sips, Ester Khin, Maxime Rotival, Ximing Sun, Rizwan Ahmed, Anissa Anindya Widjaja, Sebastian Schafer, Permeen Yusoff, Pervinder Kaur Choksi, Nicole Shi Jie Ko, Manvendra K. Singh, David Epstein, Yuguang Guan, Josef Houštěk, Tomas Mracek, Hana Nuskova, Brittney Mikell, Jessie Tan, Francesco Pesce, Frantisek Kolar, Leonardo Bottolo, Massimiliano Mancini, Norbert Hubner, Michal Pravenec, Enrico Petretto, Calum MacRae and Stuart A Cook ()
Additional contact information
Mao Wang: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Patrick Sips: Brigham and Women's Hospital and Harvard Medical School
Ester Khin: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Maxime Rotival: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital
Ximing Sun: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital
Rizwan Ahmed: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital
Anissa Anindya Widjaja: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Sebastian Schafer: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Permeen Yusoff: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Pervinder Kaur Choksi: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Nicole Shi Jie Ko: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Manvendra K. Singh: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
David Epstein: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Yuguang Guan: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Josef Houštěk: Institute of Physiology, Czech Academy of Sciences.
Tomas Mracek: Institute of Physiology, Czech Academy of Sciences.
Hana Nuskova: Institute of Physiology, Czech Academy of Sciences.
Brittney Mikell: Brigham and Women's Hospital and Harvard Medical School
Jessie Tan: National Heart Centre Singapore
Francesco Pesce: National Heart and Lung Institute, Royal Brompton Campus, Imperial College London
Frantisek Kolar: Institute of Physiology, Czech Academy of Sciences.
Leonardo Bottolo: South Kensington Campus, Imperial College London
Massimiliano Mancini: Oncological and Anatomo-Pathological Sciences, University of Rome
Norbert Hubner: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine (MDC)
Michal Pravenec: Institute of Physiology, Czech Academy of Sciences.
Enrico Petretto: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore
Calum MacRae: Brigham and Women's Hospital and Harvard Medical School
Stuart A Cook: Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12061

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