The cure for calcification
A cure has been found for a sick heart valve
Kirill Stasevich, Science and Life (nkj.ru )
One of the most common heart defects is calcification, or calcification of the aortic valve. The valve cells begin to accumulate calcium, which makes the valve less elastic, which, in turn, hinders the flow of blood from the heart to the aorta. As a result, the left ventricle of the heart suffers constant increased pressure, which eventually stretches and begins to contract worse, and then overloads begin in the left atrium. Usually in such cases it is necessary to surgically change the calcified valve. However, researchers from the Gladstone Institute of Cardiovascular Diseases, together with colleagues from the Institute of Cytology of the Russian Academy of Sciences, the Almazov National Medical Research Center and other scientific centers write in Science that they have managed to find a medicine that allows to correct a diseased aortic valve (Theodoris et al., Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease).
Calcification often occurs in those who were born with an abnormal aortic valve. Usually it has three valves that let blood from the heart into the aorta, and then close and do not let it back into the heart. But it happens that the aortic valve does not consist of three, but only of two flaps – what is called a bicuspid aortic valve.
In a third of people with such a valve, it also accumulates calcium. Observations of a family in which the bicuspid aortic valve was inherited for many generations helped to understand that in this case calcification occurs due to a mutation in the NOTCH1 gene.
But the NOTCH1 gene is included in an extensive network of cellular and molecular processes. The authors of the work came to the conclusion that it's not a single gene, but how the whole network works: the accumulation of calcium in the aortic valve begins due to the fact that some processes went wrong, and the mutation in NOTCH1 is just one of the reasons. Indeed, calcification of the valve due to mutations in NOTCH1 is only 4%, and in the remaining 96% calcification begins for other reasons.
Nevertheless, the goal of the researchers was to find a medicine that would prevent calcification of the aortic valve, regardless of the specific reason that caused it. To do this, we identified all the genes that are somehow involved in the development of pathology. Then mature human cells were converted into a stem state – that is, they received induced pluripotent stem cells capable of turning into any other type of cell – and programmed them to turn into aortic valve cells.
In such valve cells, which grew in the laboratory, the work of the genes involved in valve calcification was changed, and it was observed how much this or that gene affects the probability of calcification. Sick, calcified cells tried to treat about 1600 different molecules. Among these molecules were those that inhibit the development of bones, since calcifying cells looked as if they decided that they belonged to bone tissue.
As a result, it was possible to find a compound designated by the abbreviation XCT790, which helped cells get rid of calcium deposits, returning them to their normal state. It is important that the XCT790 molecule acted on cells that calcified for a variety of reasons, and not just because of mutations in the NOTCH1 gene. And more importantly, the experimental drug acted not only on cells in laboratory culture, but also on a real aortic valve – this was shown in experiments on mice.
The XCT790 compound not only prevented calcification of the valve, but also stopped calcification, which had already begun, and in some cases, even reversed it, that is, the valve got rid of harmful calcium. It remains to be hoped that in clinical studies, the XCT790 molecule will manifest itself from the best side, and we will finally have a drug that relieves "calcium" heart disease.
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