Crucial Molecule May Lead to Novel Therapies for Pulmonary Arterial Hypertension

Crucial Molecule May Lead to Novel Therapies for Pulmonary Arterial Hypertension

In a recent study published in the The Journal of Clinical Investigation, researchers reported to have identified a crucial factor for the development of pulmonary arterial hypertension (PAH).

The discovery identified a small non-coding RNA, called microRNA miR-140-5p, and its target molecule as potential targets for novel therapeutic approaches to help patients suffering from the fatal lung disease.

The study,“MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension” was completed by a team from the University of Sheffield in the United Kingdom.

Previous reports showed that loss of bone morphogenetic protein (BMP) signaling leads to changes in pulmonary cells and the development of PAH. Accordingly, loss of function in the Bone Morphogenetic Protein Receptor 2 (BMPR2) gene affects 80% and 20% of families and individuals with idiopathic or familial PAH, respectively.

The team of researchers at the University of Sheffield identified a specific microRNA (small, non-coding endogenous RNAs), called miR-140-5p, whose expression is down-regulated (i.e., decreased) in the blood of PAH patients. Researchers also found that inhibition of miR-140-5p promoted PAH development, while treating live rat models of PAH with a miR-140-5p mimic had a dual benefit – it prevented the development of PAH and attenuated the progression of the already established PAH disease.

The team performed further studies and identified the key target of miR-140-5p, the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), and a critical regulator of BMP signaling. Moreover, they detected in human tissues of PAH patients, an increased expression of SMURF1. Mice without SMURF1 expression were found to be protected from PAH, thereby supporting its role in the establishment of the disease.

In conclusion, the results suggest that miR-140-5p and SMURF1 are key factors in PAH, and that targeting those factors is a potential therapeutic strategy for PAH patients.

“The study suggests that either the delivery of the microRNA gene or the inhibition of SMURF1 is a viable therapeutic target. We are currently exploring opportunities to develop a drug that can block SMURF1 activity and hope to take this forward into clinical studies in the future,” said Alex Rothman, of MRC Clinical Research and the study’s first author, in a press release.

The work was completed in collaboration with science colleagues from institutions including University of Cambridge, Novartis Institute for Biomedical Research and the National Institute for Health Research Sheffield Clinical Research Facility.

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