Targeting hypoxia in diabetes associated atherosclerosis

Atherosclerosis is a major contributor to cardiovascular disease (CVD) related deaths in subjects with diabetes. Residual increased risk of CVD remains even after treatment of conventional risk factors including hyperglycaemia. Therefore, there is an unmet clinical need to develop novel therapies that can directly target the pathobiology of atherosclerotic plaque development. Hypoxia is present in advanced atherosclerotic lesions in both humans and animal models, and it is well known that hypoxia promotes atherosclerosis development. Hypoxia inducible factors (HIFs) are transcription factors that are activated in hyperglycaemic and hypoxic conditions. HIF activation regulates a transcriptional program that protect cells under hypoxic conditions. Although, previous studies have implicated the role of HIF activation in atherosclerosis, the role and mechanism of HIF activation in diabetes induced atherosclerosis is not known. Hypothesis: HIF activating small molecule drugs may attenuate atherosclerosis in diabetes. The specific aims are: 1. In vitro model mimicking hypoxic conditions in diabetes will be established in human aortic endothelial cells to test HIF activation with a specific small molecule activator of HIF. 2. Preclinical intervention studies will also be performed where Apoe-/- mice made diabetic with streptozotocin will be treated 7-12 weeks post diabetes with HIF activator to attenuate atherosclerosis in diabetes. 3. To identify post-treatment cell specific transcriptomic and epigenomic changes using single cell approaches.