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How cell clocks regulate cardiac physiology


In this interview, News-Medical talks to Research Associate Dr. Alessandra Stangherlin about her latest research that has provided new insight into the heart’s circadian rhythm.

Can you introduce yourself, tell us about your training in molecular biology and what inspired your latest research on circadian rhythms?

My name is Alessandra Stangherlin and I have long been interested in cellular circadian rhythms. I have devoted the last five years of my career to studying how osmotic homeostasis is maintained during the circadian cycle.

The first observations showed that the abundance of the soluble cytosolic protein has a circadian rhythm, with a change of 20%. If not counterbalanced, such a change in the intracellular amount of macromolecules could affect the osmotic potential of the cytosol, triggering the compensatory movement of water, with negative consequences on cell viability.

I discovered that mammalian cells import and export Na, K, and Cl with a 24 hour rate to compensate for changes in cytosolic protein. This homeostatic control mechanism allows cells to maintain constant cell volume and preserve cell viability. In cardiomyocytes, variation in ion content confers a daily rhythm intrinsic to the rate of discharge.

What does the term “circadian rhythm” mean?

The adjective “circadian” derives from the Latin words “circa” (approximately) and “dies” (day). A circadian rhythm is a behavioral, physiological or cellular phenomenon that repeats itself every 24 hours. Circadian rhythms help synchronize an organism’s physiology with the outside world and anticipate daily environmental changes in light, temperature and food availability.

Many aspects of human physiology are circadian in nature, such as the wake / sleep cycle, the release of several hormones, and cellular metabolism. Very importantly, although they can be synchronized via external inputs, circadian rhythms are self-sustaining and occur even in the absence of external time cues.

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How did we believe the heart’s circadian rhythm used to work?

The circadian rhythms of the heart rate have been known for decades. In healthy individuals, the heart rate increases in the morning and decreases at night. Until recently, circadian regulation of heart rate was primarily attributed to non-cellular autonomic mechanisms governed by the central clock located in the brain via sympathetic and parasympathetic modulation.

However, the contribution of cell clocks has never been studied. We now show that an autonomous cell clock in cardiomyocytes regulates heart rate independent of the central nervous system and systemic signals. Indeed, the discharge rate of the action potential changes between day and night in isolated cardiomyocytes in culture. Most importantly, we have found that the daily variation in HR persists in vivo under autonomous blockade.

We also believed that the concentrations of cellular ions involved in the circadian rhythm were quite constant. Why has your research contradicted this theory and how do these levels actually vary?

We’ve all learned from textbooks that the intracellular Na concentration is around 10mM, the K concentration is around 140mM, and we’ve generally assumed that they stay fairly constant. We were surprised by our results, which showed that the intracellular concentration of many ions changes during the day by about 20-30%.

Our model suggests that the net import and export of Na, K, and Cl change over the course of the circadian cycle, leading to changes in the intracellular concentration of these ions. We have identified the SLC12A family of cotransporters as important players in this process, but we do not exclude that other carriers such as VRAC may also play a role.

Can you describe how you conducted your latest research on circadian rhythms?

We have used a variety of advanced techniques, from live cell microscopy and quantum dot tracking to assess cytosolic crowding to microelectrode array technology to measure the trigger rate of the action potential. The key to discovering ionic rhythms was the use of an analytical technique called Inductively Coupled Plasma Mass Spectrometry (ICP-MS). This technique can be used to determine the elemental composition of a sample with a high degree of sensitivity and specificity and overcomes the drawbacks of current colorimetric assays and electrophysiological methods.

How has this changed our perception of the heart’s circadian rhythm?

This work has further confirmed the importance of cellular circadian rhythms in the regulation of basic cellular functions and cardiac physiology. The 24 hour rhythm in the abundance of Na, K and Cl that we have described has an important physiological implication, as it affects the electrochemical gradient of these ions across the plasma membrane. In cardiomyocytes, this modulates the action potential depolarization phase, resulting in an increased rate of discharge when intracellular ions are high (late night) and a decrease in the rate of action potential discharge when ions are weak (end of day).

Negative cardiovascular events such as stroke, myocardial infarction, and sudden cardiac death occur with a higher incidence in the morning, but the underlying causes are unknown. Our data suggests that any alteration in the buffering mechanism we have described could make the heart more vulnerable to stress in the morning when a change in demand is required.

How do you see your research influencing future treatment options for cardiovascular disease?

Future treatments could involve pharmacological or behavioral treatments to maintain our circadian rhythms. For example, maintaining a healthy daily routine of keeping the same sleep pattern, avoiding bright light before bed, and avoiding eating at night, could help keep our biological clocks in sync.

cardiovascular conditionsImage Credit: BRO.vector / Shutterstock.com

Your research has also helped explain why shift workers are more vulnerable to heart problems. What preventive measures can those who do shift work take?

Our work and others suggest that shift workers become more vulnerable to heart problems due to a lag between the brain clock and the heart clocks. The brain clock is very sensitive to ambient light, so care should be taken with exposure to light.

There are different strategies night workers could use to synchronize their body clocks with the new schedule. Most of them rely on adopting a regular sleep and lighting routine based on their chronotype (i.e., night owls may prefer to go to bed right after their shift. ). When you sleep during the day, it’s important to get at least seven hours of sleep. Pay attention to the quality of sleep (use a comfortable bed, sleep in a dark, quiet room), and avoid consuming alcohol and caffeine for a few hours before bedtime, which can reduce the quality of your sleep. sleep.

What are the implications of this research for the relationship between heart health and sleep?

Studies suggest that there is an interaction between circadian and sleep-dependent and arousal processes on heart rate. This is because the programmed release of hormones such as cortisol and melatonin, regulated by the brain’s central clock and exposure to light, modulates our sleep / wake cycle. Maintaining a regular sleep schedule and correct light exposure pattern is considered essential for keeping our clocks in sync and is most likely beneficial for heart health.

Collaboration has been a big part of your research. How important was this level of collaboration and do you think that if more researchers collaborated together, more scientific discoveries could be made?

Our work was supported by a long-standing collaboration with many academic collaborators and AstraZeneca and was highly multidisciplinary. We used a wide range of techniques, which was only possible thanks to the unique expertise of our colleagues. Having a good network of colleagues and collaborators is fundamental to develop with confidence and support the range of experiences that can be achieved.

What are the next steps for you and your research on circadian rhythms?

Next, I would like to study ion rhythms at subcellular resolution and investigate whether these rhythms are altered during aging.

Where can readers find more information?

About Dr Alessandra Stangherli

I obtained a master’s degree in pharmaceutical biotechnology and a doctorate. in Cell Biology from the University of Padua, Italy. Dr Alessandra StangherlinDuring my PhD, I focused on the regulation of cAMP and cGMP signaling and their role in cardiomyocyte contraction. In 2016, I joined Dr John O’Neill’s lab at the Molecular Biology Laboratory (LMB) in Cambridge, UK, as a research associate to study how cellular circadian clocks regulate cell physiology. I am currently a Principal Investigator at CECAD, Cologne, where I will study the regulatory mechanisms of ionic homeostasis during aging.


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