Grant: Project Grant

Cholesterol is an essential fat molecule in the body, but can cause disease if it accumulates in the wrong places. Cholesterol buildup over decades in the walls of blood vessels (arteries) leads to the blockages or "plaques" that cause heart attacks and strokes. Our laboratory reported that the main cells where cholesterol accumulates are cells lining the arteries called smooth muscle cells (SMCs). We also discovered that SMCs have a lower level of a protein they need to get rid of the cholesterol. In addition, we found that SMCs lack high enough levels of an enzyme (a type of protein) that is needed to digest the fats coming into the cells after cholesterol buildup in the artery wall. We reported that when we give this enzyme back to the SMCs, they can release the cholesterol out of the cell even though the removal protein is only present at lower levels. In the current studies we will test the different ways that increasing the amount of this enzyme can increase the removal of cholesterol from SMCs. We will determine whether directly increasing the amount of this enzyme made by the SMCs of arteries can prevent the development of plaques or reduce plaque buildup in the artery wall caused by very high blood cholesterol. We will also test whether overproducing this enzyme in the liver reduces the buildup of cholesterol in the SMCs and total plaque. This second test will require the enzyme to move through the blood and into the artery wall. By these studies we will determine whether increasing this particular enzyme is a good therapeutic strategy to help remove cholesterol from arteries, ultimately reducing heart attacks and strokes. We will also reveal how the SMCs process the excess cholesterol when that enzyme is increased. We expect these results will pave the way to the development of a new treatment to reduce heart attacks and strokes beyond what is achieved with current treatments.