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Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis
- Source :
- Diabetes. 66:2266-2277
- Publication Year :
- 2017
- Publisher :
- American Diabetes Association, 2017.
-
Abstract
- The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE−/− mouse. In vitro platelet-derived growth factor (PDGF)– and tumor necrosis factor-α (TNF-α)–induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A4), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.
- Subjects :
- 0301 basic medicine
Vascular smooth muscle
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Myocytes, Smooth Muscle
Inflammation
Muscle, Smooth, Vascular
Diabetes Complications
Mice
03 medical and health sciences
Apolipoproteins E
Mice, Inbred NOD
In vivo
Internal Medicine
medicine
Animals
Humans
Carotid Stenosis
Cell Proliferation
Platelet-Derived Growth Factor
biology
Tumor Necrosis Factor-alpha
Growth factor
Endothelial Cells
RNA-Binding Proteins
Atherosclerosis
DNA-Binding Proteins
Endothelial stem cell
MicroRNAs
Carotid Arteries
030104 developmental biology
Immunology
Cancer research
biology.protein
Tumor necrosis factor alpha
medicine.symptom
Platelet-derived growth factor receptor
Ex vivo
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....a65ae42d2f92878d2f29d86ccc6b681b
- Full Text :
- https://doi.org/10.2337/db16-1405