Why the early hours of the day in particular can be dangerous for our health

Why do asthma, heart attacks and many other health problems tend to strike in the early morning hours? A possible explanation for this mysterious phenomenon has been discovered by researchers from the laboratory of Prof. Gad Asher of the Department of Biomolecular Sciences of the Weizmann Institute of Science.

In a study published in Cell metabolismscientists discovered that an important part of our circadian clock – the 24-hour internal molecular clock that ticks in every single cell – also regulates the body’s response to oxygen deprivation. This component, which undergoes changes throughout the day and night, can influence the timing of outbreaks of diseases affected by the body’s oxygen cycle.

As breathing creatures, our ability to sense and respond to oxygen deficiency is as important to us as the air we breathe. The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who discovered hypoxia-inducible factor 1-alpha (HIF-1α), the key protein that determines how each cell responds to a lack of oxygen.

As long as there is sufficient oxygen, the protein remains unstable and is quickly broken down; but when there is a shortage of oxygen, it stabilizes, accumulates and enters the cell nuclei, where it activates numerous genes essential for responding to oxygen deprivation.

However, it turns out that HIF-1α is not the only key player. In the new study conducted in Asher’s laboratory, led by PhD student Vaishnavi Dandavate and Dr Nityanand Bolshette, the team found that the BMAL1 protein, a key component of our circadian clocks, also plays an important role in the body’s response to oxygen deficiency and is necessary for stabilizing and activating the HIF-1α protein.

Furthermore, the study also suggests that BMAL1 is more than just a “booster” and that it plays a role independent of HIF-1α in activating the body’s plan to deal with oxygen deprivation. These new findings could explain why the body’s response to oxygen deprivation and coping with various medical conditions change over the course of the day and night.

Day protein, night protein

Researchers from Asher’s lab, which has been studying the link between metabolism and circadian clocks for years, had previously found that liver tissue responds differently to oxygen deprivation at different times of the day.

To deepen their understanding of the relationship between oxygen, liver tissue and the circadian clocks, they created three groups of genetically engineered mice that failed to produce one or both of the above proteins in their liver tissue: The first group did not produce HIF-1α, the protein that regulates the response to oxygen deprivation; the second group did not produce BMAL1, the key component of the circadian clock; and the third produced neither.

The researchers then examined what happened to each group when oxygen levels were reduced. They found that in the absence of BMAL1, the HIF-1α protein failed to accumulate, as it does in a normal response to oxygen deprivation. Furthermore, they discovered that these two proteins – individually and together – are largely responsible for activating the genetic response needed to cope with oxygen deprivation.

“The mechanism we discovered, which combines both proteins, is probably the most important mechanism by which mammals cope with oxygen deprivation,” says Asher. “These and other findings helped us understand that the circadian clock not only responds to oxygen deprivation, as was already known, but that it actually activates the body’s mechanism to cope with oxygen deprivation.”

The scientists were particularly surprised to find that, unlike the mice in the control group and those whose liver tissue failed to produce either protein, HIF-1α or BMAL1, the mice lacking both proteins were very had low survival rates under 30 years. conditions of oxygen deprivation in a time-dependent manner: their mortality rates were high during the dark hours, but not under identical daytime conditions. These findings indicate that the combination of HIF-1α and BMAL1 plays a significant, time-dependent role in coping with oxygen deprivation.

“We know that BMAL1 undergoes changes over the course of the natural circadian cycle, which could explain why mortality rates vary throughout the day and perhaps also why diseases associated with oxygen deprivation are time-dependent,” says Asher.

The next phase of the research was to elucidate the cause of death in mice that had been genetically engineered not to produce either of the two proteins in their livers. The researchers were surprised to find only mild damage to the tissue, which in itself was not enough to explain the mortality.

They also found that these mice initially had low blood oxygen levels, even before being exposed to oxygen deprivation. These findings led to suspicion that the cause of death was related to damage to the lungs’ ability to absorb oxygen and not to the liver’s response to oxygen deprivation.

Many people with liver disease, regardless of severity, also develop a pathological condition called hepatopulmonary syndrome, in which the blood vessels in the lungs dilate, leading to increased blood flow in the lungs that reduces their ability to absorb oxygen.

The researchers discovered the same phenomenon in mice that lack both HIF-1α and BMAL1 in their liver. These mice are now being used as the first genetic research model of its kind for hepatopulmonary syndrome, in studies that could shed light on the mechanisms involved in this condition.

“We found increased production of nitric oxide in the lungs, which causes the blood vessels to dilate. As a result, blood flows through the lungs much faster and oxygen is not delivered efficiently,” Asher adds. “We still don’t know by what mechanisms liver damage affects lung function, but initial findings from our genetic mouse model point to an interesting group of proteins that may be part of the communication between the liver and lungs.

“In mice that developed hepatopulmonary syndrome, this communication was disrupted. If these proteins are also produced in human patients and are indeed linked to the syndrome, they could potentially serve as targets for future therapy.”