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Deregulation of microRNA-503 Contributes to Diabetes Mellitus–Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia
Open accessAbstract
Background—: Diabetes mellitus impairs endothelial cell (EC) function and postischemic reparative neovascularization by molecular mechanisms that are not fully understood. microRNAs negatively regulate the expression of target genes mainly by interaction in their 3′ untranslated region. Methods and Results—: We found that microRNA-503 (miR-503) expression in ECs is upregulated in culture conditions mimicking diabetes mellitus (high D-glucose) and ischemia-associated starvation (low growth factors). Under normal culture conditions, lentivirus-mediated miR-503–forced expression inhibited EC proliferation, migration, and network formation on Matrigel (comparisons versus lentivirus.GFP control). Conversely, blocking miR-503 activity by either adenovirus-mediated transfer of a miR-503 decoy ( Ad.decoymiR-503 ) or by antimiR-503 (antisense oligonucleotide) improved the functional capacities of ECs cultured under high D-glucose/low growth factors. We identified CCNE1 and cdc25A as direct miR-503 targets which are downregulated by high glucose/low growth factors in ECs. Next, we obtained evidence that miR-503 expression is increased in ischemic limb muscles of streptozotocin-diabetic mice and in ECs enriched from these muscles. Moreover, Ad.decoymiR-503 delivery to the ischemic adductor of diabetic mice corrected diabetes mellitus–induced impairment of postischemic angiogenesis and blood flow recovery. We finally investigated miR-503 and target gene expression in muscular specimens from the amputated ischemic legs of diabetic patients. As controls, calf biopsies of nondiabetic and nonischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and it inversely correlated with cdc25 protein expression. Plasma miR-503 levels were also elevated in the diabetic individuals. Conclusions—: Our data suggest miR-503 as a possible therapeutic target in diabetic patients with critical limb ischemia.
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“Hyperglycemia increases the expression of several microRNAs found in the endothelium, including miR-320, miR-221, miR-503, and miR-125b.”
From The Vasculature in Prediabetes (2018) · cites this paper as [146]
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Self-citation
Metadata
- Authors
- Caporali, A., Meloni, M., Völlenkle, C., Bonci, D., Sala-Newby, G. B., Addis, R., Spinetti, G., Losa, S., Masson, R., Baker, A. H., Agami, R., le Sage, C., Condorelli, G., Madeddu, P., Martelli, F., & Emanueli, C.
- Affiliations
- The Netherlands Cancer Institute (NL)
- From the Regenerative Medicine (A.C., M.M., R.A., P.M., C.E.) and Vascular Biology (G.B.S.-N.) sections, School of Clinical Science, University of Bristol, Bristol, UK; IRCCS-Policlinico San Donato, Milan, Italy (C.V.), Italian Higher Institute of Health, Rome, Italy (D.B.); IRCCS-MultiMedica, Milan, Italy (G.S., S.L., G.C.); British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK (R.M., A.H.B.); Netherlands Cancer Institute, Amsterdam, the Netherlands (R...
- ORCID
- Venue
- Circulation
- Published
- 2011-01-25
- Volume
- 123
- Issue
- 3
- Pages
- 282-291
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2112849743
- Cited by
- 397
- References
- 30
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 9 · 2023: 16 · 2022: 20 · 2021: 20 · 2020: 13 · 2019: 28 · 2018: 39 · 2017: 30 · 2016: 29 · 2015: 37 · 2014: 37 · 2013: 40 · 2012: 35
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- British Heart Foundation (PG/06/146/21946, BS/05/001, RG/09/005/27915)
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Keywords
- diabetes mellitus, endothelial dysfunction, critical limb ischemia, cyclin E1, CDC25A, high glucose, diabetic muscle, blood flow recovery, therapeutic target
- MeSH terms
- Animals, Biopsy, Cells, Cultured, Diabetes Mellitus, Experimental, Extremities, Glucose, Humans, Ischemia, Male, Mice, Inbred Strains, Umbilical Veins, Gene Expression, Muscle, Skeletal, Neovascularization, Physiologic, cdc25 Phosphatases, MicroRNAs, Intercellular Signaling Peptides and Proteins, Endothelial Cells, Mice
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