Lipoproteins and PEDF in the Vascular Complications of Diabetes

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DESCRIPTION (provided by applicant): Micro- and macrovascular disease are major causes of morbidity and premature mortality in diabetes mellitus. Our underlying hypothesis is that vascular damage is promoted by the inter-related proceses of dyslipoproteinemia, inflammation, and oxidative stress, which may in part be mediated by growth factor imbalance. "Lipoproteins and PEDF in the Vascular Complications of Diabetes", builds on data collected from interactions with the DCCT/EDIC Study Group since 1996, and the VADT Study Group since 2001, and from related vascular cell culture work. First, (in the cohort studies) we will define the role of lipoprotein subclasses defined by nuclear magnetic resonance (NMR) as markers for macro- and microvascular complications of diabetes. Lipoprotein subclasses will be related cross-sectionally and longitudinally to complication status, and to existent (concurrent) data of detailed measures of dyslipoproteinemia, inflammation, oxidative stress, and other measures of endothelial dysfunction and insulin resistance. Second, we will define associations and possible pathogenic role of circulating Pigment Epithelial Derived Factor (PEDF) in the vascular complications of diabetes. PEDF, which has anti-inflammatory, anti-oxidant and anti-angiogenic actions is implicated (as a protective factor) in diabetic retinopathy and nephropathy, but may have different actions and significance in atherosclerosis. In our human vascular cell culture work, we will employ relevant stimuli (unmodified and glycated and oxidized Low Density Lipoprotein and PEDF) to evaluate inflammation, apoptosis/proliferation, cytokine release, angiogenic responses, and NF-8B signaling There are three Specific Aims: Aim 1: To determine and compare the relationships between NMR-defined lipoprotein subclasses and cardiovascular disease, retinopathy and nephropathy in Type 1 and Type 2 diabetes; Aim 2: To determine the relationship between serum PEDF levels and complications and other risk markers; Aim 3: To compare effects of lipoproteins and of PEDF on cultured human monocyte/macrophages, aortic endothelial, smooth muscle cells and renal mesangial cells. Risk marker measures will be related to new "hard" CVD outcomes and microvascular disease progression in the DCCT/EDIC and VADT cohorts. The eventual goal is a mechanistic understanding of vascular damage in diabetes that will result in better predictive and therapeutic strategies. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Diabetes and its complications (premature heart attacks and strokes, amputations, kidney failure, blindness, and nerve damage) are epidemic in our nation and the world, and effective strategies to predict, prevent, and treat these complications are urgently needed. A better understanding of the vascular complications of diabetes is a research goal of the highest priority so that effective treatments and preventive strategies may be developed. This work, which involves ongoing collaboration with two large federally funded prospective studies of Type 1 and of Type 2 diabetes, addresses markers and mechanisms for the chronic vascular complications of diabetes.