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Evaluation of Bioenergetic Function in Cerebral Vascular Endothelial Cells
Published on: November 19, 2016
Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in
Ravinder Reddy Gaddam1,2,3, Mounika Pathuri4, Paroma Deb1,2
1Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Abstract:
MicroRNA-122-5p (miR-122) is primarily expressed in 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 endothelial cells take up miR-122 through a neuropilin-1-dependent mechanism. Aortic transcriptomic analysis implicates miR-122 role 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 potentially safer and more effective therapy.
Insights
MicroRNA-122 (miR-122) released during obesity impairs blood vessel function. Inhibiting miR-122 improves vascular efficiency and oxygen consumption in mice, suggesting a therapeutic target for diabetic vasculopathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Vascular Biology
Background:
- MicroRNA-122 (miR-122), primarily hepatic, elevates in circulation during obesity.
- miR-122 negatively impacts non-liver tissues, including vascular endothelial cells, contributing to diabetic vasculopathy risk.
Purpose of the Study:
- To investigate the role of miR-122 in regulating blood glucose and endothelial function in diet-induced obesity.
- To evaluate the therapeutic potential of a gamma-peptide-nucleic acid-based miR-122 inhibitor (γP-122-I) for diabetic vasculopathy.
Main Methods:
- Utilized high-fat diet-fed mice models.
- Administered targeted and non-targeted γP-122-I.
- Performed aortic transcriptomic analysis and assessed mitochondrial function.
- Investigated miR-122 uptake mechanism via endothelial cells.
Main Results:
- miR-122 inhibition improved endothelial function and vascular efficiency in mice.
- Targeting inhibitor to endothelial cells preserved vascular benefits but reduced metabolic improvements.
- Endothelial cells internalize miR-122 through a neuropilin-1-dependent pathway.
- miR-122 negatively affects mitochondrial respiration and electron transport chain complexes.
Conclusions:
- miR-122 plays a detrimental role in mitochondrial function and vascular health.
- γPNA-based miR-122 inhibition shows promise as a therapeutic strategy for diabetic vasculopathy.
- Understanding miR-122's mechanism in endothelial cells is crucial for targeted therapy development.
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