title: The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia.
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 hypertension. 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.
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Oliver
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Klio
authors.initials: K
authors.lastname: Maratou
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Atanur
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Dubois
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cotroneo
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Chien-Nien
authors.initials: CN
authors.lastname: Chen
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arce
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Chabosseau
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Joan
authors.initials: J
authors.lastname: Ponsa-Cobas
authors.affiliation: Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.affiliation: Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Moyon
authors.affiliation: Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.affiliation: Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan.
authors.forename: Almaz
authors.initials: A
authors.lastname: Aldashev
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001160:Arterioles / Q000378:metabolism; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D033481:Chromosomes, Mammalian / Q000235:genetics; D002908:Chronic Disease; D005260:Female; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; C000601136:Slc39a12 protein, rat; D015032:Zinc