γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet

Ravinder Reddy Gaddam; Karishma Dhuri; Young-Rae Kim; Julia S Jacobs; Vikas Kumar; Qiuxia Li; Kaikobad Irani; Raman Bahal; Ajit Vikram

doi:10.1021/acs.jmedchem.1c01831

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γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet

Journal article

Open access

Peer reviewed

γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet

Ravinder Reddy Gaddam, Karishma Dhuri, Young-Rae Kim, Julia S Jacobs, Vikas Kumar, Qiuxia Li, Kaikobad Irani, Raman Bahal and Ajit Vikram

Journal of medicinal chemistry, Vol.65(4), pp.3332-3342

02/24/2022

DOI: 10.1021/acs.jmedchem.1c01831

PMCID: PMC8883473

PMID: 35133835

Appears in UI Libraries Support Open Access

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https://doi.org/10.1021/acs.jmedchem.1c01831View

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Abstract

The blood levels of microRNA-122 (miR-122) is associated with the severity of cardiovascular disorders, and targeting it with efficient and safer miR inhibitors could be a promising approach. Here, we report the generation of a γ-peptide nucleic acid (γPNA)-based miR-122 inhibitor (γP-122-I) that rescues vascular endothelial dysfunction in mice fed a high-fat diet. We synthesized diethylene glycol-containing γP-122-I and found that its systemic administration counteracted high-fat diet (HFD)-feeding-associated increase in blood and aortic miR-122 levels, impaired endothelial function, and reduced glycemic control. A comprehensive safety analysis established that γP-122-I affects neither the complete blood count nor biochemical tests of liver and kidney functions during acute exposure. In addition, long-term exposure to γP-122-I did not change the overall adiposity, or histology of the kidney, liver, and heart. Thus, γP-122-I rescues endothelial dysfunction without any evidence of toxicity and demonstrates the suitability of γPNA technology in generating efficient and safer miR inhibitors.

Drug Design

Adiposity - drug effects

Animals

Blood Cell Count

Blood Glucose - metabolism

Body Weight

Cardiovascular Diseases - drug therapy

Diet, High-Fat

Endothelium, Vascular - drug effects

Kidney Function Tests

Liver Function Tests

Mice

Mice, Inbred C57BL

MicroRNAs - antagonists & inhibitors

MicroRNAs - blood

Muscle, Smooth, Vascular - drug effects

Peptide Nucleic Acids - adverse effects

Peptide Nucleic Acids - pharmacology

UIOWA OA Agreement

Details

Title: Subtitle: γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet
Creators: Ravinder Reddy Gaddam - University of Iowa
Karishma Dhuri - University of Connecticut
Young-Rae Kim - University of Iowa
Julia S Jacobs - Roy J. and Lucille A. Carver College of Medicine
Vikas Kumar - University of Connecticut
Qiuxia Li - University of Iowa
Kaikobad Irani - University of Iowa
Raman Bahal - University of Connecticut
Ajit Vikram - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.65(4), pp.3332-3342
DOI: 10.1021/acs.jmedchem.1c01831
PMID: 35133835
PMCID: PMC8883473
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Publisher: American Chemical Society
Grant note: DOI: 10.13039/100000968, name: American Heart Association, award: 18CDA34080125, 828081
Language: English
Date published: 02/24/2022
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984313094402771

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