Role of AP-1 transcription factor in foam cell formation in diabetes associated atherosclerosis

Atherosclerosis is a major contributor to cardiovascular disease (CVD) related premature deaths in people with diabetes. Residual increased risk of CVD remains even after treatment of standard risk factors including hyperglycaemia. Therefore, there is an unmet need of novel therapies that can directly target the pathobiology of atherosclerotic plaque development. Macrophage associated pro-atherosclerotic processes including impaired cholesterol efflux resulting in foam cell formation are important therapeutic targets in atherosclerosis. Expression of genes linked to impaired cholesterol efflux can be regulated by multiple factors including transcription factors (TFs) such as activator protein 1 (AP-1) complex. Although, previous studies have implicated the role of foam cells in atherosclerosis, the role of AP-1 TF complex in foam cell formation in diabetes induced atherosclerosis is not known. Hypothesis: Inhibiting AP-1 activity may attenuate foam cell formation resulting in reduced atherosclerosis in diabetes. The specific aims are: 1. In vitro model mimicking diabetes-induced foam cell formation will be established in human monocytes THP-1 derived macrophages to test AP-1 inhibition with an AP-1 specific small molecule inhibitor, T-5224. 2. Complementary in vitro AP-1 knockdown experiments using shRNA will also be performed. 3. Preclinical intervention studies will also be performed where Apoe-/- mice made diabetic with STZ will be treated 5-weeks post diabetes with T-5224 to attenuate atherosclerosis in diabetes and to investigate if atherosclerosis attenuation is linked to reduced foam cell formation.