Attack on plaque

We all have some degree of atherosclerosis, the narrowing of arteries caused by the buildup of plaque. When Drs. Michael Brown and Joseph Goldstein picked up the Nobel Prize in Physiology or Medicine in 1985, they paved the way for the widespread use of statin drugs that can slow this progression. Now uOttawa researcher Dr. Mireille Ouimet is looking for ways we could take this further and actually turn back the clock on atherosclerosis.

It all revolves around cholesterol—both the “bad” low-density lipoprotein (LDL) cholesterol that accumulates in the vascular wall and the “good” high-density lipoprotein (HDL) cholesterol that circulates in the blood and can remove excess cholesterol from the wall and eliminate it from the body.

“Cholesterol is an essential molecule. It’s required for life, and it’s in every single one of our cells as a central component of cell membranes,” says Dr. Ouimet, an assistant professor in uOttawa’s Department of Biochemistry, Microbiology and Immunology and a scientist and director of the Cardiovascular Metabolism and Cell Biology Laboratory at the University of Ottawa Heart Institute.

“But too much cholesterol will be toxic to the cell. Then this cell will take it out of their membranes and store it in organelles called lipid droplets. Those are the organelles that I am interested in.”

We get plenty of cholesterol from a modern Western diet, and when that is combined with cholesterol manufactured in our cells, it makes for more supply than we need. While statins halt the internal production of cholesterol, the plaques full of lipid droplets that have already built up on the arterial walls are still there, threatening to rupture and cause a heart attack or stroke. Dr. Ouimet’s work is zeroing in on how lipid droplets exit these plaques. If she can identify the mechanism, it will bring us that much closer to shrinking plaques that have already formed—effectively turning back time on cardiovascular disease.

Her search has led her to look at the brain, which contains one-quarter of the body’s cholesterol while only comprising 10% of its mass. The brain generally does not let unaltered cholesterol from the rest of the body in, or its own out. A protein called ORP-6 is expressed in the brain more than anywhere and is believed to be important in maintaining cholesterol homeostasis there. A variation in the genetic sequence for ORP-6 is associated with Alzheimer’s disease, which suggests a role in cognitive function. Dr. Ouimet and her team are looking at how cholesterol can build up in cells of the brain.

“We give our mice high-fat “McDonald’s” diets to induce the plaques, but until now we haven’t been looking at their brains,” says Dr. Ouimet.

With the help of Drs. Diane Lagace, Baptiste Lacoste and Steffany Bennett, Dr. Ouimet hopes to venture outside of her more familiar research territory and incorporate new techniques in neuroscience and lipidomics into her work to see a more complete picture of the body’s internal cholesterol economy.

“It’s a deviation away from heart disease,” says Dr. Ouimet. “But you have to go where your research takes you.”

An embellished research image from Dr. Ouimet's lab

 

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