The major goal of this renewal proposal is to define the mechanisms by which oxidative stress regulates vascular remodeling. Oxidative stress may cause cardiovascular disease by oxidation of LDL and the vessel itself. Studies with vitamin E suggest that harmful effects of oxidative stress may be reversed as shown by the reduction in myocardial infarction in the CHAOS study. They propose that the effects of oxidative stress on vascular remodeling are mediated by redox sensitive protein kinases in endothelial cells (EC) and vascular smooth muscle cells (VSMC). Specifically, they believe that the beneficial effect of """"""""outward"""""""" remodeling (increase in vessel and lumen size) are inhibited by increased production of reactive oxygen species (ROS). This hypothesis is based on three findings obtained during the previous two years of grant support. 1) They found a 3-fold increase in ROS production 2 weeks after coronary balloon injury. 2) They showed that vitamins C and E caused outward vessel remodeling which correlated with decreased ROS production by the injured vessel. 3) They defined several signal events stimulated by ROS and identified two members of Mitogen Activated Protein(MAP) kinase family ERK1/2 and the Big MAP Kinase (BMK-1)-as redox sensitive kinases. They now propose to investigate the role of BMK1 as an important redox-sensitive kinase involved in vascular remodeling. They have focused on BMK1 because it is the only redox sensitive kinase that is specifically activated by ROS and not by growth factor and cytokines; our data suggest that BMK1 is regulated by c-Src which may be a key mediator of redox-sensitive signal transduction; their data suggest that BMK1 to be highly regulated in both EC and VSMC; and it is likely that BMK1 plays an essential role in the changes in gene expression that accompany oxidative stress. The following Aims are proposed.
Aim 1 : Characterize the effect of vessel redox state on vascular remodeling in the rat carotid artery by using vitamin E deficient rats to increase ROS production.
Aim 2 : Determine the signal transduction events activated by steady and oscillatory flow in EC that stimulate BMK1 focusing on the role of c-Src and Rho.
Aim 3 : Determine the signal transduction events activated by ROS which stimulates BMK1 in VSMC focusing on the role of c-Src.
Aim 4 : Evaluate the role of BMK1 in vascular remodeling in the rat carotid by dominant inhibition using adenoviral gene transfected antisense oligonucleotide techniques. these studies should provide insight into the mechanisms by which ROS regulate remodeling and aid development of new therapeutic approaches to limit restenosis and atherogenesis.
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