Journal article
Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes
Molecular therapy. Nucleic acids, 102830
01/2026
DOI: 10.1016/j.omtn.2026.102830
Abstract
MicroRNA-122-5p (miR-122) is primarily expressed by the liver and is increasingly released into the bloodstream during obesity. It impacts the function of non-liver tissues, such as vascular endothelial cells, and increases the risk of diabetic vasculopathy. Using a gamma-peptide-nucleic acid-based miR-122 inhibitor (γP-122-I), we show that miR-122 regulates blood glucose levels and endothelial function in high-fat diet-fed mice. Targeting γP-122-I to endothelial cells retains its ability to improve vascular function but reduces metabolic benefits compared to the non-targeted version. Our results show that the endothelial cells take up miR-122 through a neuropilin-1-dependent mechanism. Aortic transcriptomic analysis implicates miR-122 in mitochondrial function. The aortas of high-fat diet-fed mice receiving an inhibitor of miR-122 were more efficient in oxygen consumption despite a decline in the expression of mitochondrial electron transport chain complexes. Supporting these findings, the overexpression of miR-122 under hyperglycemic conditions decreases mitochondrial electron transport chain respiration and mitochondria with high membrane potential, indicating its detrimental impact on mitochondrial function. These findings support miR-122 as a therapeutic target for diabetic vasculopathy and support γPNA-based miR-122 inhibition as a potential safer and more effective therapy.
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Endothelial uptake of microRNA-122 via neuropilin-1 disrupts mitochondrial respiration. γ-peptide nucleic acid–based inhibition of microRNA-122 preserves mitochondrial coupling efficiency and rescues endothelial vasorelaxation in obesity-associated prediabetes in mice.
Details
- Title: Subtitle
- Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes
- Creators
- Ravinder Reddy Gaddam - University of IowaMounika Pathuri - University of ConnecticutParoma Deb - University of IowaSubhash Dwivedi - University of IowaAnamika Vikram - University of IowaVishal Kasina - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT-06269, USAVeda S. Amalkar - University of IowaVitor Lira - University of IowaHarpreet Kaur - Louisiana State University Health Sciences Center ShreveportNirav Dhanesha - Louisiana State University Health Sciences Center ShreveportAshutosh Kumar Mangalam - University of IowaRaman Bahal - University of ConnecticutAjit Vikram - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA-52242, USA
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Nucleic acids, 102830
- DOI
- 10.1016/j.omtn.2026.102830
- ISSN
- 2162-2531
- eISSN
- 2162-2531
- Publisher
- Elsevier Inc
- Language
- English
- Electronic publication date
- 01/2026
- Academic Unit
- Neurology; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Dental Research; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9985121501102771
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