Cardiovascular (CV) morbidity and mortality are increased in humans with type 2 diabetes. Restenosis after angioplasty also occurs more frequently in diabetic patients than in nondiabetics. The altered metabolism of lipoproteins may contribute to increased CV risk and vascular remodeling in type 2 diabetics. Type 2 diabetes is thought to reduce anti-atherogenic effects of HDL and its principal protein component apolipoprotein (apo) A-I. Increasing attention is focusing on new pharmacotherapies that specifically elevate HDL cholesterol in patients at risk for atherosclerosis. In this application, we discuss the novel peptide D-4F whose design is based on structural features of apo A-I. Administration of D-4F to dyslipidemic rodents improves the quality of HDL by increasing its antioxidant activity and stimulates the formation of small HDL particles with high cholesterol uptake capacity. The obese Zucker (OZ) rat is hyperglycemic, insulin resistant and dyslipidemic and is commonly used as a model for type 2 diabetes. Intimal lesion formation is significantly increased in balloon injured carotid arteries of OZ rats compared to normoglycemic controls. This response correlated strongly with reduced plasma HDL and an increase in Tg and glucose. It is hypothesized that vasoprotective properties of HDL will limit the hyperproliferative response to balloon inflation injury in arteries of OZ rats. This may be achieved by reducing plasma concentrations of atherogenic lipoproteins and/or Tg. It is further hypothesized that D-4F exerts anti-inflammatory effects and improves glycemic control by mechanisms related to the improvement in HDL quality/function. Accordingly, we propose to test the general hypothesis that the novel apo A-I mimetic peptide D-4F reduces the exaggerated response to endoluminal injury in diabetic OZ rats. These hypotheses will be tested by 3 aims that will assess whether D-4F: 1) improves HDL quality/function by increasing its anti-oxidant capacity and reverse cholesterol transport in OZ rats; 2) inhibits the expression of proinflammatory mediators in balloon injured arteries of OZ rats; and 3) improves glycemic control in diabetic OZ rats via activation of peroxisome proliferator activated receptor-gamma signaling pathways. The proposed studies will establish the efficacy of apo A-I mimetic peptides, a novel class of drugs for the management of dyslipidemia, particularly in the context of diabetes, and will provide the rationale for the development of new treatment modalities in humans at high risk for atherosclerosis.
