Cause of hardening of the arteries – and potential treatment – identified

A team of British scientists has identified the mechanism behind the hardening of the arteries and has shown, in animal studies, that a generic drug normally used to treat acne could form effective treatment.

The team, led by Cambridge University and King's College London, discovered that a molecule thought to exist only in cells used for DNA repair is also responsible for hardening arteries, associated with dementia, heart disease, blood pressure and stroke.

There is currently no treatment for hardening of the arteries, which is caused by the build-up of bone-like calcium deposits, stiffening of the arteries and the restriction of blood flow to the organs and tissues.

Backed by funding from the British Heart Foundation, the researchers found that poly (ADP ribose), or PAR, a molecule normally associated with DNA repair, also causes calcification of the arteries.

The researchers also found that minocycline – a widely prescribed antibiotic often used to treat acne – could treat hardening of the arteries by preventing calcium formation in the circulatory system. The study, the result of more than a decade of fundamental research, is published in the journal Cell reports.

"The hardening of the arteries occurs with age and accelerates in dialysis patients, where even children develop calcified arteries.But up to now, we did not know what was controlling this process and so how to treat it, "said Professor Melinda Duer. from the Cambridge Department of Chemistry, who co-directed the research as part of a long-term collaboration with Professor Cathy Shanahan of King's College London.

"This hardening, or biomineralization, is essential for bone production, but in the arteries, it is at the root of many cardiovascular diseases and other diseases associated with aging, such as dementia," Shanahan said. . "We wanted to know what triggers the formation of calcium phosphate crystals and why it seems to focus around collagen and elastin, which make up the bulk of the artery wall."

In previous research, Duer and Shanahan had shown that PAR, normally associated with the repair of DNA within the cell, could actually exist outside the cell and was the motor of bone production. This has led the researchers to hypothesize that RAP may also play a role in biomineralisation. In addition, PARP1 and PARP2, the dominant PAR-producing enzymes, are expressed in response to damage to DNA and oxidative stress, processes associated with bone and vascular calcification.

"We could see bone signals that we could not explain, so we searched for molecules from the basic principles to understand it," said Duer.

"I thought for years that hardening of the arteries was related to DNA damage and that DNA damage is a pathway that is activated by many agents, including smoking and lipids," he said. Shanahan. "When this pathway is activated, it causes the pathologies associated with aging.If the damage is sufficient, the arteries will reflect it."

Using NMR spectroscopy, the researchers found that when cells are stressed and die, they release PAR, which binds very strongly to calcium ions. Once released, the RAP begins to mop the calcium into larger droplets that adhere to the components of the artery walls that give the artery its elasticity, where they form neat crystals and solidify, hardening the arteries.

"We could never have predicted that it was caused by the PAR," Duer said. "It was initially an accidental discovery, but we followed it and it led to potential treatment."

After discovering the links between DNA damage, PAR, calcification of bones and arteries, the researchers then investigated a way to block this pathway by using a PARP inhibitor.

"We had to find an existing molecule that was cheap and safe, otherwise it would take decades to get treatment," Shanahan said. "If something has already proven safe in humans, the drive to the clinic can be much faster."

In collaboration with Cycle Pharmaceuticals, a Cambridge-based company, researchers have identified six known molecules that they believe could inhibit PARP enzymes. Detailed experiments with these showed that the antibiotic minocycline was very effective in preventing hardening of the arteries.

"It's been 12 years of basic research to get to this point," said Duer. "We left without any hope of finding a potential treatment, there is currently no treatment and no one would have believed us if we had then announced that we were going to cure the hardening of the arteries."

This technology has been patented and licensed to Cycle Pharmaceuticals by Cambridge Enterprise, the university's marketing arm. The researchers hope to conduct a proof-of-concept trial in patients in the next 12 to 18 months.

"The calcification of blood vessels is a well-known risk factor for many heart and circulatory diseases, and can lead to high blood pressure and eventually to a life-threatening heart attack," said Professor Jeremy Pearson, deputy medical director at the British Heart Foundation. "Now, researchers have shown how the calcification of blood vessel walls occurs and how the process differs from normal bone formation, in doing so they were able to identify a potential treatment to reduce calcification of blood vessels without any adverse effects. This type of treatment would benefit many people and we look forward to the results of planned clinical trials to determine if this drug is keeping its promises. "