Clarify the mechanisms of ischemia, characteristic of a heart attack, could Russian scientists from Moscow State University, along with colleagues from Ireland.
According to the World Health Organization, cardiovascular disease is the leading cause of death worldwide. The majority of deaths related to stroke and coronary heart disease. In addition, Russian President Vladimir Putin proposed to declare 2015 the National Year of combating cardiovascular disease, because in Russia, more than 56% of deaths due to diseases of the circulatory system, and because the president’s proposal looks quite reasonable and timely.
A group of researchers from Moscow State University, as well as their Irish colleagues at the University of Cork (University College Cork) studied the early response of cells to ischemia – reduced blood supply, leading to cell death. Results published in the scientific journal Genome Biology, the impact factor is equal to 10.5.
The authors: Senior Researcher Research Institute of Physical and Chemical Biology. AN Belozersky State University and Dmitry Andreev, Doctor of Chemistry, Professor Ivan Shatsky – told of the results.
The study was made possible by the development of techniques of deep sequencing (Next Generation sequencing), which made a real revolution in the life sciences. In particular, the scientists used the method of ribosome profiling. During protein synthesis in the cell responsible ribosomes – huge macromolecular machines able to read the information encoded in the mRNA, and the resulting proteins synthesized instructions. At each time point the cell thousands of various proteins synthesized by ribosomes, precisely those necessary cell at the moment. When a change in external conditions, such as stress on the cell ribosomes can quickly switch to the other matrix RNA and begin to synthesize the proteins necessary for cell adaptation to stress.
Due to the ribosomal profiling can provide a “snapshot” of all protein synthesis in the cell at a given time.
«We have decided to use this method for the study of changes in gene expression in mammalian cells by removing oxygen and glucose, – said Dmitry Andreev. – This effect is a model for studying ischemia, because when poor circulation cells and instantly deprived of oxygen and nutrients. ”
Prolonged exposure to ischemia always leads to irreversible tissue damage in the damaged vessel and as a consequence – to cell death. However, within a short time after the stress the cells were viable, they can still be saved and avoid the damaging effects of ischemia. That is why an understanding of the processes occurring in the cell in the first hours or even minutes after ischemia, can have a very important fundamental and practical importance.
In the study, researchers examined the early response to ischemia in the first hours after stress.
It was found that within 20 minutes after the stress begin significant changes in the synthesis of certain proteins, these changes only grow in the future.
It is interesting that the strongest changes synthesis of proteins involved in mitochondrial respiratory chain: apparently, the cell tries to drastically adapt to new conditions and switch to “alternative” energy sources in order to avoid death.
The main paradigm for the regulation of respiration in the cell signaling pathway is a family of transcription factors HIF (Hypoxia Inducible Factor ). This transcription factor activates expression of several genes, for example, glucose transport, or for the formation of new blood vessels. Under normal conditions, when the oxygen in the cell is sufficient special enzymes prolyl hydroxylase permanently modify the regulatory subunit of HIF, sending it to destruction, so HIF remains off. Once the oxygen level in the cell falls below a threshold, prolyl hydroxylase, which requires oxygen for activity, off, HIF is stabilized and starts to work. HIF signaling pathway is important also because its activity is necessary for the survival of a plurality of cancerous tumors (many tumor cells are due to defects in the blood supply faced with a chronic lack of oxygen, and they have to adapt to survive in hypoxic conditions), so that HIF is very promising target for cancer therapy. To assess the interest of the scientific community to this transcription factor may be noted that since its opening in 1995 on the subject was issued more than 12 thousand. Scientific publications, if we apply a keyword search in the database PubMed.
One of the main conclusions of the work is that the changes that we are seeing, preceded transcription factors HIF response and do not overlap with them. Moreover, Russian researchers discovered and their colleagues new ways of regulation could directly affect the signaling pathway HIF: as one of the most striking cases of regulation observed by us – increasing protein synthesis UBE2S, directly involved in the degradation of HIF.
Thus, there is an older system of regulation, about which no one had ever known. Prior to the development of the method ribosome profiling did not exist approaches that could reliably detect these early changes.
«We have a lot of plans for how to develop this subject, but at the moment we do not want to they share: in this area of research is very serious competition, including from scientists of the world’s leading research centers. It should be noted a very large contribution of all team members in this work, we look forward to continued collaboration with our partners “, – summed Dmitry Andreev.
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