image: This is an image of Drs. Zsolt Bagi (foreground) and Dan Rudic. view more
Credit: Phil Jones, Senior Photographer, Augusta University
AUGUSTA, Ga. (Feb. 20, 2018) - What do bad sleep habits and stiff blood vessels have in common?
Nothing good, say scientists exploring what appears to be a direct connection between a circadian clock that isn't working as it should and an enzyme that promotes inflammation working overtime.
The connection appears to be between Bmal1, a transcription factor that senses light and drives our master circadian clock, and ADAM17, an enzyme that sets inflammation-producing proteins free from our cells to target and thicken our blood vessel walls.
The scientists, both vascular biologists at the Medical College of Georgia, are Dr. Dan Rudic, who studies the circadian rhythm that drives our sleep-wake cycle, and Dr. Zsolt Bagi, who made the connection between ADAM17 and stiff blood vessels.
Now they want to know: "Is it a direct connection?" says Rudic, who is thinking that Bmal1 may directly regulate ADAM17.
He and Bagi are co-principal investigators on a $2.2 million National Institutes of Health grant that is enabling them to explore the unhealthy relationship, with the goal of also identifying the best point to intervene.
Rudic's lab is among those that have seen the impact of a disrupted circadian rhythm on blood vessels. Mice without normal Bmal1 function have stiff blood vessels, age rapidly and die early. It essentially cuts their life span in half, from two years to one, and could potentially do the same in humans, Rudic says.
"Stiff blood vessels are probably one of the best surrogates of aging other than death," says Rudic.
In human tissue, Bagi has connected stiff blood vessels to high levels of ADAM17 and low levels of its natural inhibitor. He has watched the inflammation-producing proteins ADAM17 sets free into the bloodstream make a beeline for the heart, where they thicken and stiffen the walls of the tiny blood vessels that help feed the important muscle. Bagi's team found the same relationship in mice that they found in human blood vessels.
So the scientists put their heads together and wondered if these two causes of stiff blood vessels were connected. In fact, is the relationship between the two the primary mechanism of action for a messed up circadian clock causing stiff blood vessels?
"That is our best guess," Bagi says. They have early evidence that downregulation of the primary clock - which naturally occurs with aging as well as habits like sleeping fewer than five hours nightly, even from regularly consuming too much caffeine - prompts the unhealthy increase in ADAM17. "This is a novel and largely unexplored signal," Rudic says.
Heart disease remains the leading cause of death in the United States and stiff blood vessels are a major risk factor. They cause higher blood pressure and more difficulty delivering adequate blood and oxygen to our body, putting us at risk for heart attack, stroke, organ failure and more.
When we are young and healthy, our blood vessels have a consistency more like cooked noodles. "They are really flexible," says Rudic. With age, and/or with a dysfunctional circadian clock, our blood vessels add more collagen, a structural protein that helps provide strength to blood vessels, bone and skin, and less elastin, an also pervasive protein in our bodies that enables flexibility. In healthy blood vessels, collagen primarily resides in the adventitia, the outer most and strongest wall. In age and disease, it also moves heavily into the strong but flexible smooth muscle wall.
Events like a heart attack or habitual consumption of high-fat foods, can accelerate collagen deposition. Bagi has shown that so can high levels of ADAM17.
He and Rudic are looking at clock dysfunction and ADAM17 from many angles to answer questions like whether bringing down levels of ADAM17 reduces the stiffness associated with clock dysfunction. Bagi is working again with dysfunctional human blood vessels, using biochemical assays to this time also look at clock gene expression. "You get a footprint of what was," says Bagi, of the now disconnected blood vessels. Preliminary data indicates Bmal1 is down in this scenario, Bagi says.
Rudic is continuing to look at his Bmal1 knockout, and he is also this time looking at what happens to ADAM17 levels. His team is also looking at old mice to see if they find the inversely proportional levels of Bmal1 and ADAM17. They are looking at what happens when both ADAM17 and Bmal1 are MIA. They also are looking at what happens when they just inhibit ADAM17, which could be a good target for reducing arterial stiffness, or improve Bmal1 function. To examine the relationship from one more angle, Bagi worked with MCG Vascular Biology Center Director, Dr. David Fulton, to come up with a version of ADAM17 that's missing its enzymatic activity - and so the ability to cleave proinflammatory proteins - to see if that makes the aged mice healthier.
The master clocks in our brain control the sleep-wake cycle and can control the myriad of clocks found across our bodies, but so can other factors. Food, for example, can reset the clocks in our liver, Rudic says.
While age causes a natural decline in our clock function, some lifestyles can also alter function and accelerate negative results like arterial stiffness.
Shift work, for example, clearly disrupts the normal circadian rhythm that makes us want to sleep at night and function in the daylight. It's considered a risk factor for hypertension, inflammation and cardiovascular disease. A study published in the journal PNAS in 2016 and led by scientists at Harvard Medical School and Brigham and Women's Hospital in Boston, showed more about how. They found short-term circadian misalignment - just three days of swapping normal sleep-wake cycles - increased 24-hour blood pressure and inflammatory markers in healthy adults.
A myriad of other factors can also disrupt a healthy rhythm from frequent jet lag to eating in the middle of the night, which technically upsets our liver clocks, which can in turn impact metabolism and vascular function, Rudic says. Even consuming too many energy drinks and too much caffeine, alcohol and nicotine can disrupt our sleep and so our circadian rhythms.
The importance of a happy circadian rhythm to our well-being even has some putting automatic dimmers on their phones, Rudic says.
ADAM17 is crucial to normal blood vessel development but high levels also are suspect in diseases like Alzheimer's and arthritis. Obesity also increases levels of ADAM17.
MCG cardiothoracic surgeons Drs. Vijay Patel and Vinayak Kamath are providing fresh blood vessels and other tissue to Bagi that must be removed as part of heart surgery.
Bagi is an associate professor in the MCG Vascular Biology Center and Department of Medicine. Rudic is an associate professor in the MCG Department of Pharmacology and Toxicology and an associate member of the Vascular Biology Center.
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