Signaling molecule in exosomes may limit PAH right-heart damage
Mice without miR-21 had more right ventricular damage, apoptosis-linked proteins
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In pulmonary arterial hypertension (PAH), blood vessel cells in the lungs release exosomes, or cellular shipping containers, filled with a signaling molecule called microRNA-21 (miR-21) that are taken up by heart cells to help limit heart damage, a new study shows.
“These findings identify exosomal miR-21 as a key mediator associated with [heart damage] adaptation, and support its potential as a biomarker and therapeutic target in PAH,” the researchers wrote.
An early-access version of the study, “Exosomal miR-21 mitigates pulmonary hypertension-induced right-heart remodeling by preserves mitochondrial homeostasis,” was published in the Journal of Translational Medicine.
Studying role of miR-21 signaling molecule
In PAH, there is abnormally high pressure in the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs. This puts strain on the right ventricle, the chamber of the heart responsible for pumping blood to the lungs.
Damage to the right ventricle, or right ventricular (RV) dysfunction, is a major driver of mortality in PAH, but the molecular mechanisms that control this damage are not fully understood.
Exosomes are tiny sac-like structures naturally produced by various cell types in the body to ship molecular cargo to each other, allowing cells in different parts of the body to communicate and coordinate with each other. MicroRNAs are small pieces of RNA that regulate gene activity within cells. Several miRNAs, including miR-21, have been implicated in the growth of lung vessels, inflammation, and problems in the cells that line blood vessels.
Researchers in Taiwan previously identified miR-21 “as one of the most significantly enriched circulating miRNAs associated with clinical RV adaptation in PAH, but noted that it wasn’t known if “PAH stimuli increase the release of miR-21–containing exosomes (exosomal miR-21) from pulmonary arteries and whether these vesicles contribute to long-distance RV-pulmonary artery crosstalk.”
Here, the same team of researchers analyzed exosomal miR-21 levels in blood samples collected from the heart chambers and pulmonary arteries of 28 people newly diagnosed with PAH and four people without PAH, who served as controls. The PAH group showed significantly higher levels of NT-proBNP, a heart damage marker, and worse RV function. Those with PAH also had significantly higher levels of exosomal miR-21 in the RV and pulmonary arteries relative to the controls.
The researchers then tested lab-grown cells and found that low oxygen levels, or hypoxia, can increase the release of miR-21-filled exosomes by cells lining pulmonary blood vessels, and that these exosomes were taken up by cardiomyocytes, or heart muscle cells.
When cardiomyocytes took up exosomes containing miR-21, the heart cells were less likely to undergo hypoxia-induced apoptosis, which is a type of programmed cell death, and abnormal enlargement, or hypertrophy.
Treatment with a miR-21-mimicking molecule significantly reduced the ratio of apoptotic and hypertrophic cardiomyocytes under hypoxia, whereas a miR-21 blocker had the opposite effect.
More ventricular damage in mice without miR-21
Using a mouse model of PAH, the researchers found that animals lacking miR-21 developed more severe right ventricular damage and showed higher levels of apoptosis-associated proteins, but lower activity of mitochondria, energy-producing structures in cells.
Treating lab-grown cardiomyocytes from PAH mice without miR-21 with a miR-21-mimicking molecule “rescued the hypoxia-induced decrease in mitochondrial [activity],” wrote the researchers, who then conducted parabiosis experiments, where they surgically connected two mice with PAH-like disease so blood would pass between them, letting exosomes flow from one to the other.
Connecting miR-21-deficient mice to unaltered mice reduced right ventricle dysfunction in the animal lacking miR-21.
The findings suggest that, in PAH, blood vessel cells in the lungs release exosomes containing miR-21, which can help limit right ventricle dysfunction. Modulating miR-21’s signaling could be a useful for treating PAH, the data show, but the scientists emphasized that more research was needed.
“Our findings suggested that exosomal miR-21 attenuates cardiomyocyte apoptosis and [blood vessel] cell-derived exosomal miR-21 could be a potential therapeutic target for PAH, while more investigations are required,” they wrote.
