title: MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.
abstract: Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.
authors.forename: Alexander M K
authors.initials: AM
authors.lastname: Rothman
authors.forename: Nadine D
authors.initials: ND
authors.lastname: Arnold
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Pickworth
authors.forename: James
authors.initials: J
authors.lastname: Iremonger
authors.forename: Loredana
authors.initials: L
authors.lastname: Ciuclan
authors.forename: Robert M H
authors.initials: RM
authors.lastname: Allen
authors.forename: Sabine
authors.initials: S
authors.lastname: Guth-Gundel
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.forename: David J
authors.initials: DJ
authors.lastname: Rowlands
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C533895:MIRN141 microRNA, human; D035683:MicroRNAs; C543718:Mirn141 microRNA, mouse; C498342:SMURF1 protein, human; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases