Accelerated atherosclerosis and microvascular complications account for the greatest numbers of deaths and hospitalizations in diabetic patients. However, the molecular mechanisms responsible for these complications remain poorly understood. As a result of our work on the project supported for 3 years by a K01 award from NIDDK, we recently reported that the expression of thrombospondin-1 (TSP-1) is strikingly elevated in large vessels of Zucker rats, an animal model of type 2 diabetes, both in basal conditions and in response to injury, suggesting a role for this protein in the accelerated atherosclerosis and increased restenosis in this animal model and diabetic patients. TSP-1 has a number of well-documented proatherogenic properties including genetic and biochemical evidence. This protein is also one of the most potent anti-angiogenic agents, a function directly relevant to diabetic complications. Our preliminary data indicated that TSP-1 expression is regulated by glucose at the transcriptional level and suggested a new direction for the applicant - use of a mouse model of atherosclerosis. The applicant is submitting a competing renewal of the grant to support her training in a new experimental approach - mouse model of atherosclerosis. The overall goal of the proposed program, which represents a competing renewal application, is to elucidate specific transcriptional mechanisms responsible for the upregulation of TSP-1 expression by glucose in major cell types of large blood vessels and to test the hypothesis that increased expression of TSP-1 in the vascular wall of a mouse model contributes to the development of atherosclerotic lesions and neointima formation. The long-term objective of the project is to uncover the hyperglycemia-induced molecular mechanisms that lead to development of diabetic vascular complications.
The Specific Aims are: 1. To identify the promoter region of the TSP-1 gene and nuclear factors responsible for the transcriptional up-regulation of TSP-1 expression by glucose and wounding; 2. To demonstrate directly in the transgenic mouse model that increased expression of TSP-1 in the vascular wall contributes to the development of atherosclerotic lesions and neointima formation in response to injury. The results of these experiments will: 1) identify targets for the regulation of expression of TSP-1, a potent anti-angiogenic and pro-atherogenic protein that may contribute to vascular diabetic complications; 2) provide additional information about the molecular mechanisms for the effects of glucose in vascular cells; and 3) demonstrate directly that TSP-1 may serve as a link between diabetes and vascular complications.
