Illustration of red blood cells moving through clogged artery to indicate cholesterol build up as a result of homozygous familial hypercholesterolemia and atherosclerosis
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Targeting PERK in smooth muscle cells can block and decrease buildup of atherosclerotic plaque in mouse models, according to a new study from researchers at UTHealth Houston. Smooth muscle cells have not been a major study focus for this disease until recently.

The research was published this week in Arteriosclerosis, Thrombosis, and Vascular Biology. 

Diseases linked to atherosclerosis, such as coronary artery disease, are the leading cause of death in the United States, and nearly half of Americans with the condition don’t know they have it. Atherosclerosis can affect most of the arteries in the body, including arteries in the heart, brain, arms, legs, pelvis, and kidneys.

Atherosclerosis comprises lipid accumulation, extracellular protein deposition, and calcification in large to medium size arteries, causing stiffness of blood vessels. Certain genetic mutations and histone modification are thought to be the biological causes. Most recently, researchers Washington University School of Medicine in St. Louis discovered that the gene SVEP1 makes a protein that drives the development of plaque in the arteries.

The UTHealth Houston researchers took an emerging approach to finding root causes of this condition.

“We are trying to identify new pathways that cause atherosclerotic plaque buildup, in particular pathways that involve a certain cell type, called smooth muscle cells,” said Dianna Milewicz, MD, PhD, lead author of the study and professor and President George Bush Chair in Cardiovascular Medicine at McGovern Medical School at UTHealth Houston.

She added that, “For many years, researchers have been focused on other cell types, like endothelial cells and macrophages, but more recent studies have highlighted a role of smooth muscle cells in plaque formation. We found that if we block a specific protein in smooth muscle cells, we can effectively block the majority of plaque formation from occurring in an animal model.”

The team generated an SMC-specific Perk knockout mouse model then induced hyperlipidemia in the mice by AAV-PCSK9DY injection. Next, they fed these mice a high fat diet that caused high cholesterol levels in their blood to drive atherosclerotic plaque formation. It turned out that blocking PERK in these mice resulted in an 80% decrease of atherosclerotic plaque buildup in male mice.

“Males tend to have more of this buildup than females. This tells us that blocking PERK in smooth muscle cells is important in plaque formation. Interestingly, this protein is activated in smooth muscle cells by too much cholesterol in the cells,” Milewicz said.

Current treatments to help patients who suffer from atherosclerosis-related conditions include lifestyle and diet changes, medications such as statins and PCSK9 inhibitors, and in more severe cases, procedures to open blocked arteries. However, Milewicz says lifestyle changes may not always help, and current medications have side effects or can be prohibitively expensive.

The researchers are hopeful these findings can translate to clinical care.

“There are a lot of drugs on the market that block the smooth muscle cell pathway,” said Abhijnan Chattopadhyay, PhD, first author on the study and a research fellow in the Division of Medical Genetics at McGovern Medical School.

He added that, “Now that we know this buildup can be blocked by targeting smooth muscle cells, we can use medication that is already available and target this pathway to help patients with atherosclerotic plaque buildup. This is just another way we can block or lower the plaque buildup, especially for those who are unable to prevent atherosclerosis with lifestyle modifications or statins.”

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