Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes

Ravinder Reddy Gaddam; Mounika Pathuri; Paroma Deb; Subhash Dwivedi; Anamika Vikram; Vishal Kasina; Veda S. Amalkar; Vitor Lira; Harpreet Kaur; Nirav Dhanesha; Ashutosh Kumar Mangalam; Raman Bahal; Ajit Vikram

doi:10.1016/j.omtn.2026.102830

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Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes

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Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes

Ravinder Reddy Gaddam, Mounika Pathuri, Paroma Deb, Subhash Dwivedi, Anamika Vikram, Vishal Kasina, Veda S. Amalkar, Vitor Lira, Harpreet Kaur, Nirav Dhanesha, …

Molecular therapy. Nucleic acids, Vol.37(1), 102830

03/12/2026

DOI: 10.1016/j.omtn.2026.102830

PMCID: PMC12860614

PMID: 41630989

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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. [Display omitted] 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 Iowa
Mounika Pathuri - University of Connecticut
Paroma Deb - University of Iowa
Subhash Dwivedi - University of Iowa
Anamika Vikram - University of Iowa
Vishal Kasina - University of Connecticut
Veda S. Amalkar - University of Iowa
Vitor Lira - University of Iowa
Harpreet Kaur - Louisiana State University Health Sciences Center Shreveport
Nirav Dhanesha - Louisiana State University Health Sciences Center Shreveport
Ashutosh Kumar Mangalam - University of Iowa
Raman Bahal - University of Connecticut
Ajit 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, Vol.37(1), 102830
DOI: 10.1016/j.omtn.2026.102830
PMID: 41630989
PMCID: PMC12860614
NLM abbreviation: Mol Ther Nucleic Acids
ISSN: 2162-2531
eISSN: 2162-2531
Publisher: Elsevier Inc
Grant note: Career Development Award from the American Heart: Association-23CDA1037711 UConn Spark Grant: NIH-R01HL167773, AHA-23CDA1037711 FOEDRC Bridge-to-the-Cure fundAHA postdoctoral award: 828081, 23CDA1037711, R01HL158546
We acknowledge the Central Microscopy and Research Facility (CMRF) at the University of Iowa, Iowa City, IA. We recognize Dr. Juan E. Abrahante, University of Minnesota Genomics Center (UMGC) , MN, for assistance in submitting the transcriptomics data to the NCBI GEO database. We thank CSR Biotech (Guangzhou) Co., Ltd. for live-cell imaging using their commercial super-resolution microscope (MI-SIM) , data acquisition, SR image reconstruction, analysis, and discussion. The graphic abstract was created with BioRender.com . This work was supported by grants from the FOEDRC Bridge-to-the-Cure fund and the University of Iowa Start-up fund to Ajit Vikram, a Career Development Award from the American Heart Association-23CDA1037711 to R.R.G., and a UConn Spark Grant to R.B. Ajit Vikram. was partly supported by NIH-R01HL167773, AHA-23CDA1037711, and the FOEDRC Bridge-to-the-Cure fund. R.R.G. was partly supported by the AHA postdoctoral award (828081) and Career Development Grant (23CDA1037711) . R01HL158546 partly supported ND.
Language: English
Electronic publication date: 01/2026
Date published: 03/12/2026
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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