Heart attack switched to reverse
Biologists restored cardiac activity in mice after a heart attack
Anna Kaznadzei, N+1
Researchers from Baylor College of Medicine and the Texas Heart Institute have managed to restore cardiac activity in mice after a heart attack. To do this, they turned off one of the genes of the Hippo pathway involved in suppressing the proliferation and regeneration of cardiomyocytes and the occurrence of fibrosis of cardiac tissues. The study is published in Nature (Leach et al., Hippo pathway disability reverses systolic heart failure after infarction).
Until now, the most effective means to cope with heart failure were either the transplantation of a new organ or the implantation of an auxiliary device that sets the heart rate. At the same time, scientists do not lose hope of finding a remedy that will make the heart cells recover on their own.
During a heart attack, part of the cardiac tissues loses access to oxygen and dies, and in their place a scar formed with the help of fibroblasts that are not capable of contraction forms. As a result, the heart can no longer work as before, and the larger the lesion area, the weaker the heart muscle becomes. It is known that the Hippo – kinase cascade pathway is involved in this process, which interacts with a number of transcription factors and prevents the regeneration and proliferation of cardiomyocytes.
Scientists have been working on a line of mice with coronary heart disease. Three weeks after an artificially induced myocardial infarction that caused systolic heart dysfunction (ventricular tissue damage), the Salvador gene was turned off in such mice (Salv) encoding one of the participants of the Hippo path. The heart function of the mice was observed every two weeks using echocardiography. Six weeks after the gene was switched off, the cardiac activity in these mice was close to the cardiac activity of healthy mice. In most cases, the ventricular tissue contained significantly more cardiomyocytes, and the fibrous scar was smaller than in the control group also subjected to infarction. Synthesis of factors such as Myh7 NppA, NppB, involved in the reorganization of cardiomyocytes, in mice with Salv turned off, unlike the control group, was not started.
Analysis of the total RNA of cardiomyocytes in healthy mice, in mice after a heart attack with Salv turned off and in normal mice after a heart attack showed that the first two groups are the closest to each other. Thus, switching off the Hippo pathway leads to the fact that the heart cells seem to "not know" about the infarction and continue normal life activities, including those associated with regeneration and proliferation.
Scientists have demonstrated the particular importance of the Park2 protein, which is responsible for the "quality control" of mitochondria, in the restoration of cardiac tissue. In case of violations of its activity, "faulty" mitochondria are not culled in time, and this leads to disruption of the work of cardiomyocytes as a whole. Researchers have shown that deletion of the corresponding gene leads to serious cardiomyopathy. It turned out that after a heart attack, the synthesis of Park2 in cardiomyocytes in the control group significantly decreases, but in mice with Salv turned off, it remains normal. This is explained by the fact that the Hippo pathway is responsible for phosphorylation and exclusion of transcription factors Taz and Yap from the cell nuclei involved in the processes of cardiac tissue repair. The Yap factor, in particular, is necessary for the synthesis of Park2.
The scientists also constructed a viral vector that allows turning off the gene in any mice (in the previous part of the experiment, they worked with a specially bred genetically modified mouse line, for which it was possible to turn off the Salv gene at any time using tamoxifen). The introduction of such a vector both during a heart attack and three weeks later caused significant improvements in cardiac tissue compared to control groups.
In the future, scientists plan to investigate in more detail the effect of the Hippo pathway on the development of cardiac tissue fibrosis.
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