microRNAs tightened the scars on the heart
Pyotr Smirnov, "Newspaper.Ru»Regular jogging, swimming, hardening and breathing exercises are excellent prevention of cardiovascular diseases.
Fortunately for scientists who do not risk being left idle in the near future, few people have the time or, more likely, the willpower to follow these simple rules.
Add the first place in the ranking of causes of death and universal interest in the main muscle of our body, and you will not have any questions about why such a large number of both impassably "fundamental" and purely clinical works are devoted to heart failure. Moreover, the immediate target for the effects of the drug is often determined by the epoch: 20 years ago, the minds were excited by reactive oxygen species and nitrous oxide, then stem cells replaced them, and now there is no escape from a variety of regulatory RNA chains.
Stefan Engelhardt and his American and German colleagues were no exception: first they found microRNA-21 in the heart, and then used it to prevent heart failure.
From the very beginning of their work, the authors of the publication in Nature paid close attention not only to muscle cells, cardiomyocytes, but also to the surrounding fibroblasts – connective tissue cells that form not only ligaments, tendons, fascia, but also the "framework" of various internal organs. Due to the ability of fibroblasts to divide and even migrate a little, deep cuts are quickly tightened, and extensive damage to the mucous membranes in the stomach or nose does not become a "gateway" for infections.
But these "skills" of fibroblasts do not benefit the liver or the heart. In case of infarction or cirrhosis, the defect area is filled not with cardiomyocytes and hepatocytes, respectively, but with fibroblasts forming a kind of scar. However, such scarring can also occur gradually, when the "network" of fibroblasts increases for one reason or another, slowly displacing native cells. As a result, the functional abilities of the heart are weakened, and the risk of a "crisis" situation increases.
Engelhardt and his colleagues found that mice with early-stage heart failure, developing in the same way as humans, had significantly increased levels of microRNA-21 in heart cells. When scientists "split" the signal, they found that the amount of this RNA is minimal directly in muscle cells, and the observed total effect is achieved due to rare fibroblasts.
Why it is necessary for the latter, it became clear after several experiments in vitro: like any other microRNA, miRNA-21 has its own target – a gene whose work it blocks. In the case of miRNA-21, this is the Spry1 gene, the shutdown of which protects the cell from programmed death – apoptosis and even promotes the division of its own kind due to the production of signaling molecules – growth factors.
There is no miRNA-21 in fibroblasts of a healthy heart, which keeps their population stable, but once Spry1 is blocked (which happens, for example, with a lack of blood supply), they immediately begin to divide, even seemingly not in the most favorable conditions. As a result, already limited resources are spent not on maintaining the work of cardiomyocytes, but on the formation of a "network" of fibroblasts, which leads to further death of muscle cells.
Exactly the same pattern develops with artificial partial ligation of the aorta – the largest mammalian vessel coming out of the left ventricle of the heart. The scientists decided to treat the mice affected by this operation with a miRNA-21 antagonist – a short complementary chain capable of binding firmly to it and completely blocking it. Slightly modifying the oligonucleotide so that it could penetrate the cell membrane, Engelhardt and colleagues administered the appropriate dose intravenously. Those who received treatment had their hearts restored. Unlike the control group.
Thus, scientists not only received a new method of treatment, but also proved a new scheme of development of the disease, fundamentally different from today's views, according to which the leading role is played by decreasing and dying cardiomyocytes, whose place is occupied by fibroblasts. According to the new scheme, which has yet to be repeatedly tested, fibroblasts themselves decide when to divide and displace muscle cells.
Clinical trials, however, are not worth waiting for yet: it remains to be seen how universal this scheme is and whether it is fair for people.
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01.12.2008