Grant: Project Grant

Heart attack and stroke are the leading causes of mortality and morbidity worldwide. The most common cause of these diseases is atherosclerosis, which is when inflammation leads to cellular (leukocytes/macrophages) build up in the blood vessel, lipid (fat) deposition, and transformation of these cells into very fatty cells in the vessel wall. Platelets, which are a group of blood cells that usually help us stop bleeding, are also involved in atherosclerosis. Atherosclerotic build-up (lesions) may decrease the blood supply, rupture, and initiate platelet adhesion and aggregation, which leads to thrombosis (vessel blockage by platelets; occlusion). Vessel occlusion can occur in critical vessels (like coronary and cerebral vessels) and results in heart attack and stroke. We are interested in determining how to prevent or slow down atherosclerosis and how to control thrombosis. These are challenges both for scientists and clinicians alike. We recently found that apolipoprotein A-IV (apoA-IV), a lipid binding protein in the blood, is a new binding protein for a major platelet receptor GPIIbIIIa. We are the first lab to demonstrate that apoA-IV inhibits platelet function and thrombosis. In the proposed studies, we will continue our previous work and study how apoA-IV affects platelet function and thrombosis, and address whether the anti-inflammatory and anti-atherosclerotic effects of this protein are due to apoA-IV binding to platelets (via GPIIbIIIa) or by binding to related receptors on leukocytes. Our study will not only provide information regarding whether apoA-IV can be used as an anti-thrombotic drug, but also explore the mechanisms of how apoA-IV inhibits inflammation and atherosclerosis. Since apoA-IV production is markedly increased during lipid (particularly unsaturated fat) absorption in the gut after we eat, our study may be also able to provide new guidance for food consumption in order to prevent heart attack and stroke.