Vascular Inflammation and Advanced Glycation Endproducts

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DESCRIPTION (provided by applicant): The leading cause of morbidity and mortality in both insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is atherosclerotic cardiovascular disease. The age-adjusted incidence of myocardial infarction is six times greater in diabetic men, and four times greater in diabetic women than in nondiabetic subjects. This markedly accelerated vascular pathology cannot be fully explained by the well-described coexistence of traditional cardiovascular risk factors. Although the association of chronic hyperglycemia and diabetic micro- and macrovascular disease has been established, the mechanisms of the linkage between hyperglycemia and atherosclerotic vascular pathology have not yet been fully elucidated. Diabetes, as a disease state, presents a potentially very complex metabolic stimulus to the cellular components of the arterial wall. The functionally relevant components of the altered metabolic milieu of diabetes include not only changes in glucose and insulin levels, but may also include "secondary" metabolic abnormalities that occur as a result of the primary abnormalities in insulin and glucose metabolism. Advanced glycation endproducts (AGEs) are the late products of the modification of proteins, lipids and nucleic acids by reducing sugars. They have been implicated as an important component of the metabolic abnormalities resulting in diabetic vasculopathy. The central hypothesis of this proposal is that AGEs have an important, and potentially central, role in the accelerated vasculopathy of NIDDM and IDDM via the regulation of redox-sensitive proinflammatory cell signaling pathways. The proposed studies will systematically explore AGE-mediated regulation of redox state and proinflammatory gene products in vascular disease and determine the functionally relevant molecular events responsible for the proatherogenic effects in-vivo.