Project 463343

Diseases of the human vascular system remain leading causes of disability and death in the Western world. These diseases largely arise from atherosclerosis, which involves the formation of diseased areas called plaques within the walls of arteries that often lead to blockage of the arteries causing heart attacks or strokes. Although significant progress has been made in both our understanding of risk factors for vascular diseases as well as the development of therapies to reduce risk, much work remains to be done. Blood levels of some lipoproteins (protein/fat complexes in the blood) are risk factors for atherosclerosis; the best known is LDL (the "bad" cholesterol). The lipoprotein that we study is called lipoprotein(a) (Lp(a)), an inherited risk factor that when present in elevated levels in the blood causes heart attacks and other cardiovascular disorders. Lp(a) is very similar to LDL but contains an extra protein called apo(a), which appears to make Lp(a) harmful in ways that are different than LDL. However, it is still unknown exactly how Lp(a) contributes to atherosclerosis development and progression, and the overall objective of this project is to define the mechanisms involved. A new aspect of Lp(a) research has revealed the presence of special inflammatory lipids (fats) that are preferentially added to Lp(a). Evidence is accumulating from our group and others showing that these lipids on Lp(a) (including those on the apo(a) component of Lp(a)) negatively affect the behavior of key cells in the artery wall through stimulating inflammatory processes in these cells that are the key to atherosclerosis. We will use special tools that we have recently developed in our laboratory including a novel mouse model to find answers to what makes Lp(a) uniquely harmful. This will yield new information required to understand why Lp(a) is such a potent risk factor for heart disease and how to develop strategies to specifically reduce this risk.