This is a continuing application of a successful program project that has focused on reactive oxygen species (ROS) and their role in cardiovascular disease. The present proposal combines talents of several outstanding investigators with a new emphasis on the interplay between inflammation and oxidant stress and the manner in which these contribute to hypertension, atherosclerotic plaque formation and response to disease. Project 1 will focus on a newly recognized role of the T cell in the genesis of hypertension and will seek to determine mechanisms responsible for T cell homing. Studies will determine if interruption of T cell entry into tissues prevents hypertension. Project 2 will delineate the respective roles of plasmacytoid and myeloid dendritic cells (DCs) and their upstream signals in plaque formation. In this project, signals which act on toll-like receptors will be used to selectively activate respective DC subtypes and the consequent T cell/macrophage recruitment and activation in intact plaques will be defined The role of DCs and T cells in promoting vascular smooth muscle death, NADPH oxidase expression and ROS production will be defined and a novel therapeutic approach to suppress tissue injury in the plaque will be examined. Project 3 has arisen from a very successful ongoing collaboration among the project investigators in which a phenomenon first observed in vascular biology studies was found to be responsible for diastolic dysfunction in hypertension. Preliminary data indicates that hypertension causes oxidation of the NO synthase co-factor tetrahydrobiopterin in the heart, and that this leads to uncoupling of nitric oxide synthase and diastolic dysfunction. Studies will be performed that will delineate the cell type involved in ROS production in the heart and novel therapeutic approaches will be employed, which if successful, would provide the first direct treatment of diastolic dysfunction. A mouse that develops cardiac oxidative stress and diastolic dysfunction without hypertension will allow us to separate the effects of blood pressure lowering versus recoupling of nitric oxide synthase in improvement of diastole function. Our PPG will be supported by two Cores that will provide expertise with detection of ROS and histological analysis of relevant tissues. Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease.
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