title: miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia.
abstract: The NOS (nitric oxide synthase) inhibitor ADMA (asymmetric dimethylarginine) contributes to the pathogenesis of pulmonary hypertension. Reduced levels of the enzymes metabolizing ADMA, dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) and increased levels of miR-21 are linked to disease pathology, but the mechanisms are not understood. In the present study we assessed the potential role of miR-21 in the regulation of hypoxia-induced changes in ADMA metabolism in vitro and in vivo. Hypoxia inhibited DDAH1 and DDAH2 expression and increased ADMA levels in cultured human pulmonary endothelial cells. In contrast, in human pulmonary smooth muscle cells, only DDAH2 was reduced whereas ADMA levels remained unchanged. Endothelium-specific down-regulation of DDAH1 by miR-21 in hypoxia induced endothelial dysfunction and was prevented by overexpression of DDAH1 and miR-21 blockade. DDAH1, but not DDAH2, mRNA levels were reduced, whereas miR-21 levels were elevated in lung tissues from patients with pulmonary arterial hypertension and mice with pulmonary hypertension exposed to 2 weeks of hypoxia. Hypoxic mice treated with miR-21 inhibitors and DDAH1 transgenic mice showed elevated lung DDAH1, increased cGMP levels and attenuated pulmonary hypertension. Regulation of DDAH1 by miR-21 plays a role in the development of hypoxia-induced pulmonary hypertension and may be of broader significance in pulmonary hypertension.
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Lucio
authors.initials: L
authors.lastname: Iannone
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubois
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Lucie
authors.initials: L
authors.lastname: Duluc
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Wharton
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.affiliation: †MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.affiliation: *Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Beata
authors.initials: B
authors.lastname: Wojciak-Stothard
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP