DESCRIPTION (provided by applicant): Our overall aim is to define the specific role of arginase activity in diabetes-induced cardiovascular disease. These studies will set the stage for developing new strategies to prevent the vascular injury that leads to diabetic heart disease. Endothelial cell (EC) dysfunction is a prominent feature in the vascular complications of diabetes. Our preliminary data show impaired coronary vasorelaxation and perivascular fibrosis/hypertrophy in diabetic rats, which are associated with reactive oxygen species (ROS) formation and increased arginase activity, which diverts L-arg from eNOS to the ornithine pathway. Our data also show that high glucose and ROS increase arginase I expression and that statin HMG CoA reductase inhibitors and supplemental L-citrulline (L-cit) block the actions of diabetes in increasing ROS, inducing arginase expression and activity and causing coronary fibrosis and impaired vasorelaxation. These effects are explained by studies showing that diabetes and high glucose-induced ROS activate the small G protein RhoA, which activates Rho kinase (ROCK). ROCK in turn activates arginase and inhibits eNOS, whereas NO production inhibits the arginase/ornithine pathway and statins enhance eNOS activity, NO formation and inhibit activation of RhoA/ROCK. Additionally, our studies indicate that L-cit, which increases L-arg levels and inhibits arginase activity, maintains L-arg availability for NOS better than L-arg itself. Based on these data, we hypothesize that diabetes and high glucose cause vascular dysfunction by RhoA/ROCK-mediated activation of the arginase/ornithine pathway. Decreased L-arginine availability to eNOS uncouples the enzyme to form superoxide rather than NO which reduces vasodilation. Accelerated activity of the arginase/ornithine pathway induces perivascular fibrosis, hypertrophy, leading to vascular stiffening. This model will be examined using a combination of molecular, pharmacological and biochemical approaches to test the following hypotheses for experiments in diabetic animals, vessels and blood from diabetic patients and cultured cells. 1) Define the molecular mechanisms by which diabetes activates arginase. 2) Test whether diabetes causes impaired EC-dependent vasorelaxation by activating arginase. 3) Test whether diabetes causes vascular fibrosis, hypertrophy and stiffening by activating arginase. 4) Test whether diabetes activates the arginase/ornithine pathway by activation of RhoA/ROCK. PUBLIC HEALTH RELEVANCE: Coronary vascular heart disease which can cause heart attacks is a major health problem, which is much worse in people who have diabetes. Understanding the factors and sequence of events in diabetes which reduce blood flow to heart is critical to preventing and treating this disease. Limiting actions of an enzyme which can prevent the heart from getting enough blood and cause thickening and stiffness of heart blood vessels offers much promise for reducing the incidence of this disease.
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