microRNA against infarction

The cells that form the muscle tissue of the adult heart, known as cardiomyocytes, retain a very limited ability to divide compared to the cells of the child's heart. After a myocardial infarction, some cardiomyocytes die and, due to the inability of the remaining cells to reproduce, scar tissue forms in their place. Over time, this can lead to the development of heart failure in a person.

In their latest work, researchers at the Boston Children's Clinic, working under the guidance of Professor Da-Zhi Wang, demonstrated the possibility of restoring the regenerative abilities of heart tissue using microRNAs - small molecules that regulate the functioning of genes and are present in large quantities in the tissues of the developing heart.

In 2013, Wang and his colleagues identified a family of microRNAs, called miR-17-92, whose members regulate the proliferation of cardiomyocytes. In their new work, they found that 2 molecules of this family, namely miR-19a and miR-19b, are the most powerful and potentially effective candidates for post-infarction therapy.

In experiments on mice, the authors tested two methods of delivering microRNAs to cells. One method involved intravenous administration of lipid-coated microRNAs to animals to facilitate passage through the cell membrane. The second method involved the introduction of therapeutic microRNA into a gene therapy vector, the structure of which provided selective penetration into heart cells, followed by the introduction of the drug directly into the infarction zone.

When administered to animals with simulated myocardial infarction, the gene therapy drug miR-19a/b had both immediate and long-term protective effects. In the early phase, that is, during the first 10 days after a heart attack, microRNAs reduced acute cell death and suppressed an inflammatory immune response that worsened tissue damage. Studies have shown that the introduced microRNAs suppressed the activity of many genes involved in these processes.

In the long term, the hearts of the treated mice differed from the hearts of the control group animals by a large volume of healthy tissue, a lower degree of scarring and better contractility, as evidenced by an increase in the left ventricular shortening fraction detected during an ultrasound examination of the heart. In addition, the severity of dilated cardiomyopathy was reduced – stretching and thinning of the heart muscles, ultimately leading to a weakening of the contractility of the heart.

Left: cross-sections of the mouse heart 2 months after therapy. In animals injected with miR-19a/b, the amount of cardiac muscle (green) is greater relative to the amount of scar tissue (red). Scale division = 2 mm. Right: quantitative comparison of the volume of scar tissue after injection of miR-19a/b.
Control group, n = 5, experimental group, n = 4.

According to the authors, the primary goal of therapy is to save and protect the heart from long-term damage. In the future, apparently, microRNAs contribute to the proliferation of cardiomyocytes.

In addition to simultaneous exposure to multiple genetic targets, microRNAs have another advantage over traditional gene therapy: they do not linger in the heart tissue for a long time, while having a long-term effect. According to the authors, they gave mice one injection at the moment when the heart needed it most, after which they periodically assessed the levels of microRNA expression in the heart tissue. A week after administration, the expression of these molecules decreased to normal values, but their protective effect remained for more than a year.

Even with systemic administration, most of the microRNAs moved into the damage zone. However, the authors believe that the specificity of therapy should be optimized, since microRNAs can affect other organs and tissues. The next stage of the work will be testing the therapy on larger animal models, after which it will be possible to proceed to planning clinical trials.

According to the authors, each organism synthesizes a certain amount of miR-19a/b, so the proposed therapy will stimulate an already existing mechanism. In general, microRNAs have a huge potential in the treatment of diseases of the cardiovascular system.

Article by Feng Gao et al. The therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction is published in the journal Nature Communications.

Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Boston Children's Hospital: Protecting damaged hearts with microRNAs.