Drugs that were first developed 40 years ago, and then abandoned, could help prevent clots from breaking off and clogging the artery, they report.
When people have too much cholesterol in their blood, immune cells called macrophages seize fatty particles and try to drag them out through the walls of the artery. But they are too big, get stuck and eventually the macrophages are overwhelmed and die.
These plugs of dead cells are what causes atherosclerosis – the hardening and clogging of the arteries.
In two papers published in the Proceedings of the National Academy of Sciences and Nature Cell Biology this week, Dr Ira Tabas of Columbia University in New York and colleagues showed they had found the mechanism that kills the cells, and a drug that may stop the process.
“In order to get atherosclerosis, you need two things going on – you need high levels of LDL (low-density lipoprotein or ‘bad’ cholesterol) in the blood and you need events in the arterial wall,” Tabas said in a telephone interview.
“Statins are utterly fantastic at lowering LDL,” he said. But they only lower the risk of stroke or heart attack by about 30 percent.
Old drug, new tricks
Tabas believes a drug that could stop the macrophages from dying and clogging up the arteries in the first place would work in tandem with statins and similar drugs to prevent heart disease.
When a macrophage gobbles up a piece of cholesterol, it is moved to a part of the cell called the endoplasmic reticulum. This is the machine responsible for making the cell’s proteins, and making proteins is what cells must do to survive and function.
Tabas believes a drug that could stop the macrophages from dying could help prevent heart disease.
“This causes the endoplasmic reticulum to function poorly,” Tabas said. “That, in turn, sets up a death programme in the cell.”
It turns out there is a drug that stops the cholesterol from getting into the cells in the first place.
“In the late 1950s and early 1960s, people learned one enzyme, if blocked, could block cholesterol biosynthesis,” Tabas said.
But drugs that blocked the enzyme only worked at high doses and caused side-effects in animals such as cataracts, so they were never developed.
Tabas found that an extremely low dose of the drugs, particularly one called U18666A, specifically prevents cholesterol from getting into the endoplasmic reticulum.
This could offer a route to treating heart disease with few side effects. The more specific a drug’s action, and the lower the dose needed, the less likely it is to cause side effects.
Pfizer now owns the rights to U18666A, but Tabas’s group has patented the application and is working with Richmond, California-based Berlex Biosciences to develop a drug that takes similar action.
In the genes
The study also raises the question of whether some people may genetically resist heart disease. A genetic defect also prevents cholesterol from getting into cells.
In children with two copies of the “bad” gene it causes a deadly nerve condition called Niemann-Pick C disease. But Tabas wonders whether people with just one copy of the “bad” gene might be protected from heart disease.
He is starting a study with parents of Niemann-Pick C patients – who may have just one mutated copy of the gene – to see if they have a lower risk of clogged arteries.