Abstract

The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1,2,3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.

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Acknowledgements

This research was supported by successive grants from British Heart Foundation to M.R.W. and L.Z. (PG/95170, PG/98018, PG/2000137, PG/04/035/16912, PG/12/61/29818, PG/10/59/28478 and RG/10/16/28575). G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1) and a Royal Society Research Merit Award. T.A. acknowledges support from European Research Council Advanced Grant ERC-2010-AdG, number 268880. We thank A. I. Garcia-Diaz for advice on genotyping techniques and R. Edwards for advice on antibody production. We thank C. Haley for discussions on the rat genetic map.

Author information

Author notes

    • Timothy J. Aitman

    Present address: Centre for Genomic and Experimental Medicine, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

    • Lan Zhao
    •  & Eduardo Oliver

    These authors contributed equally to this work.

Affiliations

  1. Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

    • Lan Zhao
    • , Eduardo Oliver
    • , Olivier D. Dubois
    • , Emanuele Cotroneo
    • , Chien-Nien Chen
    • , Lei Wang
    • , Cristina Arce
    •  & Martin R. Wilkins
  2. Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

    • Guy A. Rutter
  3. Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

    • Joan Ponsa-Cobas
    •  & Jorge Ferrer
  4. Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK

    • Klio Maratou
    • , Santosh S. Atanur
    • , Pauline L. Chabosseau
    •  & Timothy J. Aitman
  5. Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK

    • Benjamin Moyon
    •  & Zoe Webster
  6. Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan

    • Almaz Aldashev
  7. Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA

    • Maria G. Frid
    •  & Kurt R. Stenmark

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Contributions

L.Z. and M.R.W. were principal investigators on grants from the British Heart Foundation, developed concepts and supervised the project. L.Z., M.R.W. and E.O. designed and implemented the experiments. T.A. gave conceptual advice on the congenic program and whole-genome sequencing. L.Z., M.R.W., T.A., K.M., E.O. and O.D.D. conducted the congenic breeding program. S.S.A. analysed whole-genome sequence data and performed the Polyphen analysis. L.Z., E.O. and O.D.D., with the support of B.M. and Z.W., generated the ZIP12 transgenic rat. L.Z., E.C. and L.W. performed immunohistochemistry and immunofluorescence. E.O. conducted the in vitro cell culture experiment. C.A. and E.O. performed the angiogenesis assay. G.R. supervised and E.O. and P.L.C. conducted the intracellular labile zinc measurement experiments. C.-N.C. and E.O. performed ChIP–PCR. J.P.-C. and E.O. cloned the HRE construct and performed luciferase reporter assays. M.G.F., K.R.S. and A.A. provided cattle and human lung sections. E.O. performed statistical analysis. L.Z., M.R.W. and E.O. interpreted the data and wrote the manuscript. T.A., G.R., J.F., S.S.A. and K.D. edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Lan Zhao.

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DOI

https://doi.org/10.1038/nature14620

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