Low-density lipoprotein (LDL) is commonly called “bad cholesterol” because it builds up along the walls of the arteries, forming plaques that can cause deadly blockages. But what if a key player in that inflammatory, plaque-building process also had the ability to switch roles, opening up and healing the arteries instead of blocking them?
A new finding by scientists at NYU Langone Medical Center, published in the Journal of Clinical Investigation, sheds light on the process by which just that scenario might be possible. And their insight could point to new ways to reduce arterial plaque formation.
Immune cells called monocytes are at the center of the NYU research. Monocytes flock to cholesterol deposits, where they either choose to become inflammatory forces—contributing to plaque buildup—or they become healing cells instead. Monocytes that worsen the inflammatory response become cells called M1 macrophages, while those that dampen inflammation are called M2 macrophages.
The NYU scientists confirmed that when it comes to bringing about the crucial switch to M2 versus M1 macrophage, timing is everything. When monocytes arrive in plaques that are regressing, they become healing M2 macrophages—in essence controlling inflammation and preventing dangerous plaque ruptures, according to a statement from NYU.
The NYU team identified specific cells called Ly6Chigh monocytes that are able to change from taking on an inflammatory role to becoming healers instead. Now they’re working on identifying the signals that tell those monocytes to become M2 macrophages. They published their latest findings in the Journal of Clinical Investigation.
"A race is underway to develop treatments that enhance the decision of human monocytes to become M2 macrophages in cases where the disease has not yet caused clot formation, at which point it becomes irreversible," said Edward Fisher, M.D., Ph.D., director of the Marc and Ruti Bell Vascular Biology and Disease Program at NYU Langone Medical Center, in a statement.
Fisher’s team has some candidates in mind already, including immune signaling proteins interleukin-4 and interleukin-13. They are also experimenting with nanoparticles that are inspired by high-density lipoprotein (HDL), called “good cholesterol” because of its ability to remove LDL from plaques and shuttle it to the liver, where it is destroyed.
Cholesterol-lowering statins can keep LDL at bay, but they don’t go very far in reversing damage that builds up in arteries over time. PCSK9 inhibitors were hailed as more powerful cholesterol-lowering contenders when they hit the market a couple of years back. And just last week, scientists in Europe published promising preclinical data showing that an experimental vaccine may be able to inhibit the PCSK9 enzyme and significantly lower LDL levels.
But even PCSK9-focused efforts can’t reverse arterial damage enough to lessen the risk of heart attacks and other consequences of ruptured arterial plaques, Fisher says. That’s what the NYU team is hoping to do. "We need the next generation of drugs to go beyond cholesterol lowering to address the immune reaction to accumulated cholesterol, and to dismantle plaques as part of reversing or regressing mature disease," Fisher said.