How a heart attack kills a person
Researchers from MSU have clarified the mechanisms,
related to the development of ischemic disease
Vladimir Koryagin, <url>According to the World Health Organization, cardiovascular diseases are the leading cause of death worldwide.
At the same time, most deaths are associated with strokes and coronary heart disease. In addition, Russian President Vladimir Putin proposed declaring 2015 the National Year of the Fight against Cardiovascular Diseases, because in Russia more than 56% of deaths are associated with diseases of the circulatory system, and therefore the president's proposal looks quite rational and timely.
A group of researchers from MSU, as well as their Irish colleagues from the University of Cork (University College Cork) studied the early response of cells to ischemia – a decrease in blood supply leading to cell death. The results are published in the scientific journal Genome Biology, the impact factor of which is 10.5 (Andreev et al., Oxygen and glucose deprivation induces widespread alterations in mRNA translation within 20 minutes, in the public domain).
The authors of the work, Dmitry Andreev, senior researcher at the Belozersky Research Institute of Physico-Chemical Biology of Moscow State University, and Professor Ivan Shatsky, Doctor of Chemical Sciences, told about the results obtained.
The research became possible thanks to the development of deep sequencing methods (Next Generation sequencing), which made a real revolution in the life sciences. In particular, scientists used the ribosomal profiling method. Ribosomes are responsible for protein synthesis in the cell – huge macromolecular machines capable of reading information encoded in matrix RNAs and synthesizing proteins according to the instructions received.
At any given time, thousands of ribosomes in a cell synthesize various proteins, and exactly those that are needed by the cell at the moment. When external conditions change, for example, during a stressful effect on a cell, ribosomes are able to quickly switch to other matrix RNAs and begin synthesizing proteins necessary for the cell to adapt to stress. Thanks to ribosomal profiling, it is possible to obtain an "instant snapshot" of all protein synthesis in a cell at a given time.
"We decided to use this method to study changes in the expression of mammalian cell genes when oxygen and glucose are removed," Dmitry Andreev said. "This effect is a model for the study of ischemia, because when blood circulation is disrupted, cells are instantly deprived of both oxygen and nutrients."
Prolonged exposure to ischemia always leads to irreversible tissue damage in the area of the damaged vessel and, as a consequence, to cell death. However, for a short time after stress, the cells are still viable, they can still be saved and the destructive effects of ischemia can be avoided. That is why understanding the processes occurring in the cell in the first hours or even minutes after ischemia can be of very important fundamental and applied importance.
In the study, scientists studied the early response to ischemia during the first hour after stress. It turned out that within 20 minutes after stress, significant changes in the synthesis of certain proteins begin, these changes only increase in the future. It is very interesting that the synthesis of proteins involved in the mitochondrial respiratory chain changes the most: apparently, the cell is trying to adapt sharply to new conditions and switch to "alternative" energy sources in order to avoid death.
The main mechanism of regulation of respiration in the cell is the signaling pathway of transcription factors of the HIF family (Hypoxia Inducible Factor). This transcription factor activates the expression of a number of genes responsible, for example, for the transport of glucose or for the formation of new blood vessels. Under normal conditions, when there is enough oxygen in the cell, special enzymes of prolyl-hydroxylase constantly modify the regulatory subunit of HIF, sending it to destruction, thus HIF remains switched off. As soon as the oxygen level in the cell falls below the threshold value, the prolyl-hydroxylases, which need oxygen for activity, turn off, HIF stabilizes and begins to work.
The HIF signaling pathway is also very important because its activity is necessary for the survival of many cancerous tumors (many tumor cells, due to defects in blood supply, face a chronic lack of oxygen, and they have to adapt to hypoxia conditions to survive), therefore HIF is a very promising target for anti-cancer therapy. To assess the interest of the scientific community in this transcription factor, it can be noted that since its discovery in 1995, more than 12 thousand scientific publications have been published on this topic, if you apply a keyword search in the PubMed database.
One of the main conclusions of the work is that the changes that we observe precede the response of HIF transcription factors and do not overlap with them. Moreover, the new regulatory pathways discovered by Russian researchers and their colleagues can directly affect the HIF signaling pathway: for example, one of the most striking cases of regulation discovered by us is an increase in the synthesis of the UBE2S protein, which is directly involved in the HIF degradation process.
Thus, there is an earlier system of regulation that no one knew about before. Prior to the development of the ribosomal profiling method, there simply were no approaches that could reliably detect such early changes.
"We have a lot of plans on how to develop this topic, but at the moment we would not like to share them: there is very serious competition in this field of research, including from scientists from the world's leading research centers. It is necessary to note the very great contribution of all members of the team to this work, we hope to continue collaboration with our colleagues," Dmitry Andreev summed up.
Portal "Eternal youth" http://vechnayamolodost.ru06.05.2015