Cancer Drug Reduces Atherosclerosis Inflammation and Plaque

A new Yale study has identified a promising therapeutic avenue for atherosclerosis, a condition caused by inflammation and plaque buildup in arteries.

Martin Schwartz, PhD, Robert W. Berliner Professor of Medicine (Cardiology) and the study’s principal investigator, investigates how the mechanical forces from blood flow and pressure affect the cells lining the arteries and how cell responses to forces contribute to cardiovascular disease. Atherosclerosis predominantly impacts regions of the arteries that bend or branch, creating disturbances in blood flow dynamics that activate cells’ inflammatory pathways and eventually lead to plaque buildup.

In a study published Aug. 31 in Proceedings of the National Academy of Sciences, Schwartz’s team, led by associate research scientist Divyesh Joshi, PhD, has now found that a protein complex called Polycomb Repressive Complex 2 (PRC2) is associated with disturbed blood flow, and that it inhibits anti-inflammatory mechanisms in the arteries that mitigate atherosclerosis.

By blocking PRC2, the team successfully reduced harmful plaque in animal models of the disease.

“By inhibiting PRC2, we boost protective pathways that reduce inflammation and could protect people from plaque rupture in atherosclerosis,” Schwartz says.

Atherosclerotic plaques are present in nearly all adults in developed countries. They are usually asymptomatic because a protective fibrous cap forms over the plaques. But if the cap weakens and ruptures, it triggers the formation of a blood clot that can lead to a heart attack or stroke. Plaques vulnerable to rupture tend to have a thinner cap or exhibit heightened inflammation.

Scientists believe there are three types of factors driving atherosclerosis. The first are metabolic risk factors, including elevated cholesterol and blood sugar. Inflammation is another—individuals with autoimmune or other inflammatory diseases are at a higher risk for the disease.

An important but overlooked third factor, Schwartz says, is the biomechanics of blood flow through the arteries. In places where the arteries are straight tubes, the blood flow activates protective, anti-inflammatory genes. Where arteries curve sharply, disturbing blood flow, there are fewer of these protective factors and increased inflammation.

The cells lining the arteries—called vascular endothelial cells—have receptors that detect blood flow. Previous research in Schwartz’s laboratory has shown that blocking those receptors can inhibit inflammatory processes and enhance protective ones. In the new study, the researchers investigated the underlying mechanisms of the inflammation associated with disturbed blood flow.

First, they used previously published datasets to investigate genes that interact with anti-inflammatory genes in endothelial cells, and then identified those that promote disease. These analyses revealed that genes associated with PRC2, a protein complex that inhibits gene expression, were strongly associated with suppression of certain anti-inflammatory genes.

“PCR2 is understood to be pro-inflammatory in vascular endothelial cells,” Joshi says.

The researchers also studied gene expression in human endothelial cells exposed to normal and disturbed blood flow. These experiments confirmed that genes associated with PRC2 are upregulated during disturbed blood flow where inflammation tends to be higher.

However, when the researchers treated endothelial cells with tazemetostat, a drug that inhibits PRC2 and was previously used to treat cancer, they found that inflammatory signals were reduced. The findings suggest targeting PRC2 could be a treatment for atherosclerosis.

To explore PRC2 inhibition as a therapeutic avenue, the researchers developed animal models of the disease and tested the effects of tazemetostat. They found that the drug slowed plaque growth and reduced the amount of vulnerable plaque.

“It takes an unstable plaque and turns it into a more stable form that is no longer at risk of rupture,” Schwartz says.

Since conducting the study, the manufacturers of tazemetostat have withdrawn it from the market due to emerging evidence that patients who take the drug have a slightly increased risk of secondary cancers. But there are other PRC2-inhibiting drugs that may be similarly useful for treating atherosclerosis, the researchers note.

“This is a potential path forward to treating patients,” Schwartz says.