Scientists solve the mystery of hardening arteries, and find solution in a common drug

A landmark study, led by a team of scientists from King's College London and the University of Cambridge, has described the mechanism responsible for the hardening of arteries. The research also points to a common antibiotic as a potential new treatment to prevent this condition.

As we age, calcium deposits tend to build up in the walls of our arteries. This arterial stiffening is associated with a number of diseases, from heart attack to stroke and dementia. Until now scientists did not know exactly what was causing these calcium aggregations in arteries.

"This hardening, or biomineralization, is essential for the production of bone, but in arteries it underlies a lot of cardiovascular disease and other diseases associated with aging like dementia," explains Cathy Shanahan, a researcher from King's College London. "We wanted to find out what triggers the formation of calcium phosphate crystals, and why it seems to be concentrated around the collagen and elastin which makes up much of the artery wall."

Using a technique called nuclear magnetic resonance spectroscopy, the scientists discovered the culprit behind the entire process was a molecule called PAR, or poly(ADP ribose). It was revealed that PAR is produced when a cell dies, and once released it begins mopping up calcium ions until they ultimately aggregate into crystals and stick onto artery walls.

"We never would have predicted that it was caused by PAR," says Melinda Duer, co-lead on the new research. "It was initially an accidental discovery, but we followed it up – and it's led to a potential therapy."

Seeking that potential therapy led the researchers to investigate a series of molecules that could block the release of PAR, and they ultimately homed in on a commonly used antibiotic called minocycline. Animal experiments revealed high doses of minocycline blocked the production of PAR and subsequently inhibited calcification of the arteries.

"We had to find an existing molecule that is cheap and safe, otherwise, it would be decades before we would get a treatment," says Shanahan. "If something has already been shown to be safe in humans, the journey to the clinic can be much faster."

Of course this doesn't immediately translate to minocycline becoming a new treatment for heart disease and stroke. The effective dosage tested in these experiments reached as high as 50 mg/kg, whereas a high dose for humans would currently be considered around 5 mg/kg. So instead of suggesting minocycline itself could be a useful treatment, the study more conclusively affirms that strong PAR inhibition can effectively block the process of calcium mineralization in arterial walls.

Interestingly, this is not the first time minocycline has been suggested to have beneficial side effects outside of its regular function as an antibiotic. Research last year discovered minocycline can prevent the protein build-up associated with some neurodegenerative diseases and possibly enhance lifespan, at least in early animal tests. Again, it is unclear exactly how effectively this discovery can translate into human treatments, especially as it isn't clear how safe the antibiotic is as a long-term treatment.

The researchers behind this new study do note they are planning a "proof of principle trial" in human patients sometime over the next year or two but it is unclear whether they will be using minocycline directly or a different kind of PAR inhibitor.

The new research was published in the journal Cell Reports.

Source: University of Cambridge

A landmark study, led by a team of scientists from King's College London and the University of Cambridge, has described the mechanism responsible for the hardening of arteries. The research also points to a common antibiotic as a potential new treatment to prevent this condition.

As we age, calcium deposits tend to build up in the walls of our arteries. This arterial stiffening is associated with a number of diseases, from heart attack to stroke and dementia. Until now scientists did not know exactly what was causing these calcium aggregations in arteries.

"This hardening, or biomineralization, is essential for the production of bone, but in arteries it underlies a lot of cardiovascular disease and other diseases associated with aging like dementia," explains Cathy Shanahan, a researcher from King's College London. "We wanted to find out what triggers the formation of calcium phosphate crystals, and why it seems to be concentrated around the collagen and elastin which makes up much of the artery wall."

Using a technique called nuclear magnetic resonance spectroscopy, the scientists discovered the culprit behind the entire process was a molecule called PAR, or poly(ADP ribose). It was revealed that PAR is produced when a cell dies, and once released it begins mopping up calcium ions until they ultimately aggregate into crystals and stick onto artery walls.

"We never would have predicted that it was caused by PAR," says Melinda Duer, co-lead on the new research. "It was initially an accidental discovery, but we followed it up – and it's led to a potential therapy."

Seeking that potential therapy led the researchers to investigate a series of molecules that could block the release of PAR, and they ultimately homed in on a commonly used antibiotic called minocycline. Animal experiments revealed high doses of minocycline blocked the production of PAR and subsequently inhibited calcification of the arteries.

"We had to find an existing molecule that is cheap and safe, otherwise, it would be decades before we would get a treatment," says Shanahan. "If something has already been shown to be safe in humans, the journey to the clinic can be much faster."

Of course this doesn't immediately translate to minocycline becoming a new treatment for heart disease and stroke. The effective dosage tested in these experiments reached as high as 50 mg/kg, whereas a high dose for humans would currently be considered around 5 mg/kg. So instead of suggesting minocycline itself could be a useful treatment, the study more conclusively affirms that strong PAR inhibition can effectively block the process of calcium mineralization in arterial walls.

Interestingly, this is not the first time minocycline has been suggested to have beneficial side effects outside of its regular function as an antibiotic. Research last year discovered minocycline can prevent the protein build-up associated with some neurodegenerative diseases and possibly enhance lifespan, at least in early animal tests. Again, it is unclear exactly how effectively this discovery can translate into human treatments, especially as it isn't clear how safe the antibiotic is as a long-term treatment.

The researchers behind this new study do note they are planning a "proof of principle trial" in human patients sometime over the next year or two but it is unclear whether they will be using minocycline directly or a different kind of PAR inhibitor.

The new research was published in the journal Cell Reports.

Source: University of Cambridge