Grant: Project Grant

Atherosclerosis is the buildup of lipids (fat) in the blood vessel walls, this can block the artery, interrupt the blood flow and cause heart attack or stroke. It is initiated by damage to the innermost layer of the vessel wall that is in contact with blood. This layer of the vessel wall is made up of a single layer of endothelial cells (ECs) that are organized in a manner similar to cobblestones, forming a tightly controlled barrier controlling the transfer of the material circulating in the blood (including fat, inflammatory cells, etc.) into the vessel wall and the tissue. Damage to the endothelial cells allows a less restricted passage of fat particles and inflammatory cells into the vessel wall, which, along with other factors, causes damage to the arterial wall, attracting more inflammatory cells to this site. The main inflammatory cells are macrophages, which act like 'garbage collectors' and swallow the cholesterol/fat particles in the vessel wall to 'clean up' the area. But by doing so, they become filled with 'fat' and die. The dead fat-filled macrophages accumulate in various spots along the arterial wall, forming atherosclerotic plaques. Our research has identified a protein (ADAM17) that is increased in atherosclerosis. Our preliminary data show that if ADAM17 levels are reduced in ECs, the severity of atherosclerosis is reduced even if the blood cholesterol remains high. We will use genetically modified mice lacking ADAM17 only in ECs to determine the mechanism of its function. We will also investigate how reducing ADAM17 in ECS can beneficially affect other cells in the vessel wall. Finally, we will use custom-made nanoparticles to deliver material (siRNA) to specifically inhibit Adam17 synthesis in ECs (Adam17siRNA), as a treatment for mice with atherosclerosis. Findings from this study will provide a promising novel therapy for patients in whom blood cholesterol-lowering drugs (statins) are not effective or possible.