RGD Reference Report - MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. - Rat Genome Database

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MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

Authors: Rothman, Alexander M K  Arnold, Nadine D  Pickworth, Josephine A  Iremonger, James  Ciuclan, Loredana  Allen, Robert M H  Guth-Gundel, Sabine  Southwood, Mark  Morrell, Nicholas W  Thomas, Matthew  Francis, Sheila E  Rowlands, David J  Lawrie, Allan 
Citation: Rothman AM, etal., J Clin Invest. 2016 Jul 1;126(7):2495-508. doi: 10.1172/JCI83361. Epub 2016 May 23.
RGD ID: 329337371
Pubmed: PMID:27214554   (View Abstract at PubMed)
PMCID: PMC4922709   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI83361   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MIR140HumanPulmonary Arterial Hypertension severityIEP miRNA:decreased expression:blood (human)RGD 
Mir140MousePulmonary Arterial Hypertension severityISOMIR140 (Homo sapiens)miRNA:decreased expression:blood (human)RGD 
Mir140RatPulmonary Arterial Hypertension severityISOMIR140 (Homo sapiens)miRNA:decreased expression:blood (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mir140  (microRNA 140)

Genes (Mus musculus)
Mir140  (microRNA 140)

Genes (Homo sapiens)
MIR140  (microRNA 140)


Additional Information