An acne drug could protect against heart attacks and stroke by preventing arteries from hardening, scientists say.
Atherosclerosis occurs when calcium deposits build-up in the vessels, causing them to stiffen and restricting blood flow to vital organs.
But experts found molecules in the antibiotic minocycline can block the pathway that causes calcium to build-up in the arteries.
The drug, often prescribed to treat acne, was ‘highly effective’ at preventing plaque from forming in rats considered at risk of the condition.
However, it was an accidental discovery, as the academics had set out to investigate why arteries lose their elasticity.
The research was carried out by a team of scientists at the University of Cambridge and King’s College London.
It was co-led by Professor Melinda Duer, of Cambridge’s department of chemistry and Professor Cathy Shanahan, of King’s cardiovascular division.
Atherosclerosis, and the cardiovascular diseases it leads to, is the single biggest cause of death in the developed world.
The build-up of plaque is responsible for one in three fatalities, according to the Heart Research Institute.
‘Artery hardening happens to everyone as they age and is accelerated in patients on dialysis, where even children develop calcified arteries,’ Professor Duer said. ‘But up until now we haven’t known what controls this process and therefore how to treat it.’
Professor Shanahan added: ‘This hardening, or biomineralisation, is essential for the production of bone.
‘But in arteries it underlies a lot of cardiovascular disease and other diseases associated with ageing like dementia.
‘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.’
The team previously found the enzyme PAR, associated with DNA repair inside cells, can also exist outside cells and plays a role in bone production.
This led them to hypothesise PAR may also lead to biomineralisation – the scientific term for the hardening of the arteries.
PAR enzymes are also expressed following DNA damage and ‘internal stress’, which are associated with the hardening of both bones and arteries.
‘We could see signals from bone we couldn’t explain, so we looked for molecules from first principles to figure it out,’ Professor Duer said.
After analysing the molecular structure of cells, the researchers discovered they release PAR.
PAR binds strongly to calcium ions and ‘mops them up’ into larger droplets. These then attach to the substances inside artery walls that make them flexible.
The droplets eventually form solid crystals, which harden the arteries, the team wrote in the journal Cell Reports.
‘We never would have predicted it was caused by PAR,’ Professor Duer said.
‘It was initially an accidental discovery, but we followed it up – and it’s led to a potential therapy.’
Having discovered the links between PAR, bone and atherosclerosis, the researchers investigated how to block this pathway via a PARP inhibitor.
‘We had to find an existing molecule that is cheap and safe, otherwise, it would be decades before we would get a treatment,’ Professor Shanahan said.
‘If something has already been shown to be safe in humans, the journey to the clinic can be much faster.’
Working with Cycle Pharmaceuticals, the researchers identified six molecules they thought may inhibit PARP enzymes.
They then tested these molecules, which included those found in minocycline, on rats with chronic kidney disease (CKD). CKD has been linked to atherosclerosis.
Results revealed the antibiotic was highly effective at preventing the rodents’ arteries from hardening.
‘It’s been 12 years of basic research to get to this point,’ Professor Duer said. ‘We set out with absolutely no expectation of finding a potential treatment.
‘There is no treatment currently and nobody would have believed us if we had said at that point we were going to cure hardening of the arteries.’
The therapy has been patented and licensed to Cycle Pharmaceuticals. The researchers hope to carry out the first trials in atherosclerosis sufferers in the next 12-to-18 months.
Professor Jeremy Pearson, associate medical director of the British Heart Foundation, added: ‘Blood vessel calcification is a well-known risk factor for several heart and circulatory diseases.
‘It can lead to high blood pressure and ultimately, a life-threatening heart attack.
‘Researchers have shown how calcification of the walls of blood vessels takes place and how the process differs from normal bone formation.
‘By doing so, they have been able to identify a potential treatment to reduce blood vessel calcification without any adverse effects on bone.
‘This type of treatment would benefit many people and we eagerly await the results of the anticipated clinical trials looking at whether this drug lives up to its early promise.’
11 June 2019