James R. Stone, MD, PhD
Director of Cardiovascular Pathology
Massachusetts General Hospital
Assistant Professor of Pathology
Harvard Medical School
Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. The laboratory is seeking to understand the biochemical processes resulting in atherosclerosis in order to combat this pervasive disease. Atherosclerosis is characterized by the development of necrotic/lipid cores within the intima of arteries at particular sites in the circulation. These necrotic/lipid cores form in the setting of a pre-existing intimal hyperplasia, characterized by the proliferation of smooth muscle like cells in the intima. The laboratory is investigating both the signal transduction mechanisms responsible for the pre-atherosclerotic intimal hyperplasia as well as the factors stimulating the formation of intimal necrotic/lipid cores.
Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane bound NADPH oxidases. These low physiologic levels of hydrogen peroxide are mitogenic, stimulating vascular cell growth and proliferation. The mechanisms by which low endogenous levels of hydrogen peroxide stimulate cellular proliferation are currently poorly understood. The laboratory is using proteomic approaches with cultured vascular cells to identify signal transduction pathways activated by low physiologic levels of hydrogen peroxide.
Intimal hyperplasia, the pre-cursor lesion for atherosclerosis, forms both in vessels that are prone to develop atherosclerosis and in vessels remarkably resistant to atherosclerosis. The laboratory is using proteomic approaches to identify and characterize the components of intimal hyperplasia specific to atherosclerosis-prone arteries to elucidate the mechanisms leading to the formation of the necrotic/lipid cores characteristic of atherosclerosis.
Stone Lab Website
Stone Lab Website
Specific projects in the laboratory include elucidation of the biochemical pathways by which low levels of hydrogen peroxide stimulate cell proliferation in the vessel wall, and determination of the vascular extracellular matrix alterations in humans that promote the development of atherosclerosis.