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

Accepted version
Peer-reviewed

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Type

Article

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Authors

Rothman, Alexander MK 
Arnold, Nadine D 
Pickworth, Josephine A 
Iremonger, James 
Ciuclan, Loredana 

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.

Description

Keywords

Adult, Aged, Animals, Humans, Hypertension, Pulmonary, Hypoxia, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Middle Aged, Phenotype, Pulmonary Artery, Rats, Rats, Sprague-Dawley, Rats, Wistar, Signal Transduction, Ubiquitin-Protein Ligases

Journal Title

J Clin Invest

Conference Name

Journal ISSN

0021-9738
1558-8238

Volume Title

126

Publisher

American Society for Clinical Investigation
Sponsorship
British Heart Foundation (None)