Title: The role of platelet granule secretion in acute thrombosis and atherosclerotic vessel remodeling
Description: Heart attacks and strokes are the leading causes of death in the U.S. and are increasingly common worldwide. Platelet-mediated thrombosis triggers acute clinical events (e.g. myocardial infarction) in patients with atherosclerosis. Platelets also play a role in the complex cascade of events which follow endothelial injury (arterial remodeling, restenosis) and in the development and progression of atherosclerosis. However, the mechanisms through which platelets modulate thrombosis and atherosclerotic remodeling are not completely understood. Activated platelets secrete pro-thrombotic and pro-inflammatory molecules from their intracellular granules. We hypothesize that secretion of these potent cell-activating agents from platelet granules at sites of vascular injury is critical to acute thrombosis and also mediates arteriosclerotic vascular remodeling after injury. The development of platelet secretory granules occurs in the megakaryocyte. Genetic defects in platelet granule development cause platelet storage pool deficiency syndromes in humans and animals. Therefore we used two mouse models with impaired platelet granule secretion due to genetic deficiencies in (1) Rab geranyl geranyl transferase (RabGGTase), α subunit, and (2) Hermansky-Pudlak Syndrome-3 protein (HPS3p) to investigate the importance of platelet granule secretion in arterial thrombosis, vascular wall changes after acute arterial injury, and development of atherosclerosis. We found impaired platelet granule (alpha and dense) development as well as reduced platelet secretion and aggregation in RabGGTase-deficient mice. RabGGTase deficiency also markedly protected mice from injury-induced thrombotic occlusion in vivo.

HPS3p-deficient mice have platelet dense granule storage pool deficiency, but apparently normal alpha granules. The HPS3p-defiecient mice were crossed with ApoE-knockout mice to introduce the dense granule deficiency into a mouse model prone to atherosclerosis. The HPS3p-deficient mice were markedly protected from arterial thrombotic occlusion. They also exhibited reduced neointima formation post-injury, which was characterized by fewer infiltrating inflammatory cells. Finally, HPS3-deficiency reduced atherosclerosis in the aortas of high-fat fed mice. These findings suggest that platelet granule secretion may be a dual regulator of acute thrombosis and atherosclerotic remodeling in response to arterial wall injury.