Weizmann Institute of Science scientists have discovered why the small hours of the night may be prone to disaster
Why do asthma, heart attacks and many other diseases tend to break out early in the morning? It is possible that one of the explanations for the mysterious phenomenon was discovered in the laboratory of Prof. Gad Asher in the Department of Biomolecular Sciences at the Weizmann Institute of Science. In the article thatRecently published in the scientific journal Cell metabolism, The research group revealed that a central component of our biological clock - that internal molecular clock of about 24 hours that "ticks" in every cell - also regulates the body's response to lack of oxygen. This component changes throughout the day and night and may play a role in timing the onset of diseases that are affected by the oxygen cycle in the body.
As breathing creatures, the ability to sense and respond to a lack of oxygen is as essential to us as air to breath. In 2019, the Nobel Prize in Medicine was awarded to scientists who discovered a key player that controls the response of every cell in the body to lack of oxygen: HIF-1α. As long as oxygen is abundant, this protein is unstable and breaks down quickly, but when there is a lack of oxygen, it stabilizes, accumulates and enters the cell nucleus - where it activates a plan to deal with the event through the activation of many genes that are essential to react to the lack of oxygen.
But it turns out that HIF-1α is not alone. In the new study, doctoral student Vishnavi Dandabetta and Dr. Nitinad Bolshet from Prof. Asher's laboratory discovered that the BMAL1 protein - that central component of our biological clock - plays a significant role in the body's coping with a lack of oxygen, and is actually necessary for the stabilization of the HIF-1α protein and the execution of its function. Moreover, the study shows that BMAL1 is not only an "amplifier player", it also has an independent role independent of the HIF-1α protein, in the activation of the program to deal with lack of oxygen.
These new findings may explain why the body's response to lack of oxygen and its response to various medical conditions changes throughout the day and night.
Day proteins, night proteins
Prof. Gad's laboratory, which has been researching the relationship between metabolism and biological clocks for years, previously recognized that the liver tissue reacts to a lack of oxygen in a time-dependent manner. To deepen the understanding of the triangle oxygen-liver-biological clock, they created three groups of genetically modified mice that do not produce certain proteins in their liver tissue: without HIF-1α – the protein that regulates the response to lack of oxygen; Without BMAL1 - a central component of the biological clock mechanism - and without both together, and check what happens to these groups of mice under low oxygen conditions.
The researchers discovered that in the absence of BMAL1, HIF-1α does not accumulate as it should in response to a lack of oxygen. Moreover, they found that the two proteins, individually and together, are responsible for the bulk of the activation of the gene expression program that is necessary to cope with oxygen deficiency. "It is likely that the mechanism that was revealed, and which involves the two proteins, is the main mechanism for dealing with a lack of oxygen in mammals," says Prof. Asher. "These and other findings led us to the understanding that the biological clock mechanism does not only respond to the lack of oxygen as was known until now - it actually activates the mechanism for dealing with the lack of oxygen."
Decreased oxygen levels
The researchers were particularly surprised to find that, in contrast to the control mice or mice lacking HIF-1α or BMAL1 in the liver tissue, the mice that lacked both proteins in the liver showed very low survival in response to the hypoxic conditions in a time-dependent manner: the mice showed high mortality rates during the hours of darkness, while during The light they survived the exact same conditions very well. These findings indicate that the cooperation between BMAL1 and HIF-1α is of great importance in dealing with the absence of oxygen in a time-dependent manner. "We know that during the natural circadian cycle BMAL1 changes, which may explain the variation in mortality throughout the day, and possibly also the fact that diseases affected by a lack of oxygen erupt in a time-dependent manner," explains Prof. Asher.
Damage to the lungs, not just the liver
In the next step, the scientists traced the cause of death of the transgenic mice without the two proteins in the liver, and were surprised to see only a slight damage to the tissue - one that cannot by itself explain the mortality. They also noticed that the blood oxygen levels in these mice were low to begin with - even before they were exposed to low oxygen conditions. These findings raised the suspicion that the cause of death was related to impaired oxygen absorption in the lungs and not to the liver's coping with a lack of oxygen.
Among patients with liver disease, from mild disease to extensive disease, liver-lung syndrome (HPS) often develops. In this syndrome, the blood vessels in the lung expand, which causes a rapid flow of blood through the lungs and impairs oxygen absorption. The researchers also found the same phenomenon in mice lacking HIF-1α and BMAL1 in the liver. Those mice are now the first genetic research model of its kind for this syndrome and may in the future shed light on the mechanisms involved in it.
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