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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo
Samarjit Das1, Djahida Bedja2, Nathaniel Campbell1
1Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Abstract:
MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play a powerful role in various cardiovascular diseases. Recently, we have demonstrated that a microRNA (miR-181c) can be encoded in the nucleus, processed to the mature form in the cytosol, translocated into the mitochondria, and ultimately can regulate mitochondrial gene expression. However the in vivo impact of miR-181c is unknown. Here we report an in-vivo method for administration of miR-181c in rats, which leads to reduced exercise capacity and signs of heart failure, by targeting the 3'-end of mt-COX1 (cytochrome c oxidase subunit 1). We cloned miR-181c and packaged it in lipid-based nanoparticles for systemic delivery. The plasmid DNA complexed nanovector shows no apparent toxicity. We find that the mRNA levels of mitochondrial complex IV genes in the heart, but not any other mitochondrial genes, are significantly altered with miR-181c overexpression, suggesting selective mitochondrial complex IV remodeling due to miR-181c targeting mt-COX1. Isolated heart mitochondrial studies showed significantly altered O2-consumption, ROS production, matrix calcium, and mitochondrial membrane potential in miR-181c-treated animals. For the first time, this study shows that miRNA delivered to the heart in-vivo can lead to cardiac dysfunction by regulating mitochondrial genes.
Insights
We developed an in-vivo method to deliver microRNA-181c (miR-181c) to the heart in rats. This led to heart failure by targeting mitochondrial genes, specifically mt-COX1, impacting cardiac function.
Area of Science:
- Molecular Biology
- Cardiovascular Biology
- Mitochondrial Biology
Background:
- MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression.
- miRNAs play significant roles in cardiovascular diseases.
- miR-181c has been found in mitochondria, but its in vivo cardiac function is unknown.
Purpose of the Study:
- To investigate the in vivo impact of miR-181c on cardiac function.
- To establish a method for in vivo delivery of miR-181c to the heart.
- To determine the molecular targets and consequences of miR-181c in the heart.
Main Methods:
- Systemic delivery of miR-181c using lipid-based nanoparticles in rats.
- Analysis of cardiac function, exercise capacity, and heart failure signs.
- Measurement of mitochondrial gene expression, oxygen consumption, ROS production, matrix calcium, and membrane potential.
Main Results:
- In vivo administration of miR-181c resulted in reduced exercise capacity and heart failure symptoms.
- miR-181c selectively targeted and altered mRNA levels of mitochondrial complex IV genes, specifically mt-COX1.
- Mitochondrial studies revealed significant changes in oxygen consumption, ROS production, matrix calcium, and membrane potential.
Conclusions:
- In vivo delivered miR-181c can induce cardiac dysfunction by regulating mitochondrial gene expression.
- This study demonstrates the potential of targeting mitochondrial genes with miRNAs for therapeutic or research purposes in cardiovascular disease.
- miR-181c's ability to regulate mitochondrial complex IV suggests a novel mechanism for cardiac remodeling and dysfunction.
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