New study shows potential to reverse arterial blockages to avoid heart attacks and strokes

Researchers at New York University Langone Medical Center in New York, NY, have found that an immune reaction may be the key to reversing arterial blockages that could cause heart attacks and strokes. These findings are published in the Journal of Clinical Investigation.

This mouse study focused on reversing the effects low-density lipoprotein (LDL) cholesterol, which is deposited into the blood vessel walls. By age 40, many people have inflamed “wounds” in their arteries—called plaques—that can rupture to cause blood clots that block arteries.

“Even the latest, most potent cholesterol-lowering drugs, PCSK9 inhibitors, let alone widely used statins, cannot fully reverse damage done to arteries over time, and so they can’t prevent roughly 500,000 heart attacks per year in the United States,” says lead study author Edward Fisher, MD, PhD, Director of the Marc and Ruti Bell Vascular Biology and Disease Program at NYU Langone. “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.”

The NYU Langone-led research team has zeroed in on the molecular events that occur in arteries during regression of atherosclerotic plaques. Once deposited into arteries, LDL triggers the body’s immune system. Immune cells in the bloodstream, called monocytes, swarm to cholesterol deposits, and become either inflammatory or healing cell types based on signals there.

Past research has shown that monocytes become M1 macrophages that amplify immune responses, increase inflammation, and secrete enzymes that gnaw at plaques until they rupture in situations where disease is worsening in a plaque.

The current study confirmed that monocytes arriving in plaques where disease is regressing instead become M2 “healing” macrophages, which dampen inflammation and prevent the ruptures that precede clotting.

When mice were engineered to lose the ability of monocytes to become M2 macrophages, they could no longer achieve normal disease regression, the authors write.

After surgically transplanting plaques from diseased mice into the arteries of healthy mice, the research team saw a marked drop in cholesterol levels. This drop has been shown to trigger a second benefit in mice, where monocytes automatically become M2 instead of M1 macrophages as plaques rapidly regress.

New imaging techniques may be able to detect changes in the type and number of macrophages in plaques in the near future, but it is currently not known whether cholesterol lowering alone triggers this M2 switch in humans. In the meantime, if researchers can understand how to boost the switch to M2, then a number of clinical applications may become possible as assessment methods are discovered.

“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 Dr. Fisher, the Leon H. Charney Professor of Cardiovascular Medicine at NYU Langone.

The same blood-borne Ly6C^high monocytes, once thought of only as precursors to “inflammation-prone” M1 macrophages, were shown to instead become anti-inflammatory M2 cells when they arrive in a regressing plaque in this study. After identifying the class of cells from which M2 macrophages arise, the team is now seeking to identify the local signals that tell monocytes to become M2.

The candidates now include the immune signaling proteins interleukin-4 (IL-4) and interleukin-13 (IL-13), which have been linked by past studies to the M2 decision. These interleukins are known to turn on the STAT6 pathway, which sends this protein to the nucleus. From there, it turns on genes that direct a monocyte to become a M2 macrophage. Researchers confirmed that blocking the action of STAT6 reduced the number of M2 macrophages in regressing plaques.

Dr. Fisher’s team is already experimenting with nanoparticles based on the structure of “good cholesterol,” which removes cholesterol from plaques and delivers it to the liver for destruction.

One version of their nanoparticle delivers IL-4 to plaques as well. The next step is a study of nanoparticles in pigs. Success with that model may set the stage for human trials.

To read more about this study, click here.