miRNA-140-5p: new avenue for pulmonary arterial hypertension drug development?

• Published in: Epigenomics Vol. 8; no. 10; pp. 1311 - 1313
• Main Authors: Rothman, Alexander MK, Rowlands, David J, Lawrie, Allan
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.10.2016
• Subjects: Bone morphogenetic protein receptor type II; Drug development; Drug therapy; Epigenetics; Estrogens; Growth factors; Heart; Humans; Hypertension; Hypertension, Pulmonary; Interleukin 6; Lung diseases; Medical research; Menopause; MicroRNAs; miR140-5p; miRNA; Mitochondria; Mutation; Osteoprotegerin; Pathogenesis; Patients; Platelet-derived growth factor; Professional development; pulmonary arterial hypertension; remodeling; Smurf1; Toxicity; Transplantation; Tumor necrosis factor; Tumor necrosis factor-TNF; ubiquitination; Vasodilators; Veins & arteries; miRNA; remodeling; Smurf1; ubiquitination; pulmonary arterial hypertension; miR140-5p
• ISSN: 1750-1911; 1750-192X
• DOI: 10.2217/epi-2016-0089

Current pharmacological treatments are primarily vasodilators, as their mechanism of action and offer a significant increase in survival but there remains no cure other than transplantation. Since the identification of mutations in the gene encoding BMPR2 in familial cases of PAH over 15 years ago (3), there are now well-established additional mechanistic insights into disease pathogenesis including interaction with growth factors including PDGF, 5-HT, inflammation including, IL-6 (4 ,5), TNF superfamily members OPG (6-8) and TRAIL (9 ,10), mitochondria metabolism, estrogen as well as epigenetic regulation of these pathways (1 ,11). [...]increasing confidence that Smurf1 is important in human disease examination of explanted lung tissue from patients with idiopathic and heritable PAH demonstrated increased expression of Smurf1 within the pulmonary vasculature. Compared with a therapeutic miR140-5p mimetic, an inhibitor of Smurf1 may be more tractable where challenges such as rapid miRNA degradation, low cellular penetration and target engagement particularly in complex remodeled pulmonary vasculature of PAH patients and potential for liver toxicity with miRNA therapeutics all may limit ability to progress promising molecules to the clinic and ultimately represent barriers to achieving clinical efficacy. Financial and competing interests disclosure Funding for this research was provided by a Medical Research Council Clinical Research Training Fellowship (AMK Rothman: MR/K002406/1); Medical Research Council Career Development Award (A Lawrie: G0800318); British Heart Foundation Senior Basic Science Fellowship (A Lawrie: FS/13/48/30453) and British Heart Foundation Project Grant (PG/11/11629288).