MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents

Tianji Chen; Miranda R Sun; Qiyuan Zhou; Alyssa M Guzman; Ramaswamy Ramchandran; Jiwang Chen; Dustin R Fraidenburg; Balaji Ganesh; Mark Maienschein-Cline; Karl Obrietan; J Usha Raj

doi:10.1016/j.omtn.2022.06.008

MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents

Mol Ther Nucleic Acids. 2022 Jun 22:29:204-216. doi: 10.1016/j.omtn.2022.06.008. eCollection 2022 Sep 13.

Authors

Affiliations

¹ Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
² Cardiovascular Research Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
³ Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁴ Flow Cytometry Core, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁵ Research Informatics Core, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁶ Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA.

Abstract

MicroRNAs (miRNA, miR-) play important roles in disease development. In this study, we identified an anti-proliferative miRNA, miR-212-5p, that is induced in pulmonary artery smooth muscle cells (PASMCs) and lungs of pulmonary hypertension (PH) patients and rodents with experimental PH. We found that smooth muscle cell (SMC)-specific knockout of miR-212-5p exacerbated hypoxia-induced pulmonary vascular remodeling and PH in mice, suggesting that miR-212-5p may be upregulated in PASMCs to act as an endogenous inhibitor of PH, possibly by suppressing PASMC proliferation. Extracellular vesicles (EVs) have been shown recently to be promising drug delivery tools for disease treatment. We generated endothelium-derived EVs with an enriched miR-212-5p load, 212-eEVs, and found that they significantly attenuated hypoxia-induced PH in mice and Sugen/hypoxia-induced severe PH in rats, providing proof of concept that engineered endothelium-derived EVs can be used to deliver miRNA into lungs for treatment of severe PH.

Keywords: MT: Non-coding RNAs; engineered extracellular vesicles; microRNAs; pulmonary artery smooth muscle cells; pulmonary hypertension; pulmonary vascular remodeling.

Abstract

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