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Cited by 75RNA Interference and Gene DeliveryMicroRNA in disease regulationAtherosclerosis and Cardiovascular Diseases

Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression

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Zhang, Xinbo, Rotllan, Noemi, Canfrán-Duque, Alberto, Sun, Jonathan, Toczek, Jakub, Moshnikova, Anna, Malik, Shipra, Price, Nathan L. +8 more·2022·Circulation Research
DOI 10.1161/circresaha.121.320296PMC PMC9640270
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Abstract

Background: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. Methods: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. Results: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes ( Col2a1, Col3a1, Col1a2, Fn1 , etc) and tissue inhibitor of metalloproteinase 3 ( Timp3 ) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. Conclusions: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.

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Authors
Zhang, X., Rotllan, N., Canfrán-Duque, A., Sun, J., Toczek, J., Moshnikova, A., Malik, S., Price, N. L., Araldi, E., Zhong, W., Sadeghi, M. M., Andreev, O. A., Bahal, R., Reshetnyak, Y. K., Suárez, Y., & Fernández-Hernando, C.
Affiliations
  • Yale University (US)
  • Vascular Biology and Therapeutics Program (X.Z., N.R., A.C.-D., J.S., J.T., N.L.P., E.A., W.Z., M.M.S., Y.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.
  • University of Rhode Island (US)
  • University of Connecticut (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-06-24
Volume
131
Issue
1
Pages
77-90
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.121.320296
PMC
PMC9640270
OpenAlex
W4229458511
Cited by
75
References
10
Citations by year
2026: 13 · 2025: 20 · 2024: 19 · 2023: 18 · 2022: 5
FWCI
5.06
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Heart, Lung, and Blood Institute (R35HL135820, R35HL155988)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K01DK120794)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
pHLIP, pH-responsive peptides, atherosclerosis regression, antisense oligonucleotide delivery, macrophage targeting, atherosclerotic plaque, collagen deposition, fibrosis, TIMP-3, MMP-12, monocytes/macrophages, miRNA-based therapy, targeted drug delivery
MeSH terms
Antagomirs, Humans, Macrophages, MicroRNAs, Atherosclerosis, Plaque, Atherosclerotic

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