The mysterious mechanism behind the hardening of arteries may have been solved, researchers have revealed, in a study that also suggests the first potential preventive drug for the condition linked to heart attack, dementia and stroke. Arteries harden as calcium becomes deposited in the elastic walls of the vessels, a process that happens as we age and is exacerbated for patients with diabetes or kidney disease. Stiffening can also occur as calcium becomes deposited in fatty plaques in the arteries – a condition called atherosclerosis. The mechanism that causes the calcium to be deposited has been difficult to unpick, but now scientists say they have the answer: it is triggered by a molecule, called poly(ADP-Ribose) or PAR, that is produced when the cells, or the DNA inside them, are damaged. That, they say, makes sense: ageing, high blood pressure, smoking and fatty plaques are risk factors for the stiffening of the arteries and are linked to damage to cells or even their DNA. The team say the new discovery could prove important for patients.
“If [the calcification process] is driven by cells that means you can actually treat it,” said Cathy Shanahan, Professor of Cell Signalling and co-author of the study from King’s College London. Writing in the journal Cell Reports, the team describe a series of experiments involving bone-forming tissues from sheep and blood vessel cells from cows, as well as human arteries. The results reveal that where PAR is found in high levels outside cells, calcium deposits are also found. What’s more, these areas were found to be rich in markers of cell death, or cells with DNA damage. They also found PAR binds to calcium, as well as to certain proteins found between cells in the walls of arteries and bone-forming tissues. As a result, the team propose that PAR, which has previously been linked to DNA repair and cell death, plays a key role not only in bone formation but in hardening of the arteries.
Crucially, further experiments, including in rats, showed that if an enzyme involved in producing PAR is blocked, calcium is no longer deposited in arteries even when DNA is damaged. They also found an existing antibiotic used for acne, called minocycline, can do the job. “People have been studying this for decades and this is the first potential therapy ever,” said Prof Melinda Duer, co-author of the study from the University of Cambridge. However, the team say that while it offers hope that artery stiffening might be prevented in some at-risk groups, questions remain. Duer stressed that individuals should continue to avoid lifestyles habits that can contribute to artery stiffening, including smoking and poor diets. Shanahan agreed. “What we don’t know is whether it is going to work on people who have already got a lot of calcification,” she said.
Paul Evans, professor of cardiovascular science at the University of Sheffield, said drugs such as minocycline that switch off PAR production might one day help patients with arterial disease. “There is considerable interest in the development of PAR inhibitors for cancer and other diseases,” he said. “It is possible that some of these medicines could benefit patients with cardiovascular disease by lessening the symptoms of angina and by reducing the likelihood of heart attack or stroke.”
Credit: Nicola Davis for The Guardian, 11 June 2019.