Vascular complications of diabetes are the main and a long-standing interest of my group. Hyperglycemia is an independent risk-factor for development of macrovascular and microvascular complications. High blood glucose regulates the expression of a number of vascular genes implicated in atherogenesis, angiogenesis, and endothelial dysfunction. Our goal is to identify the molecular pathways activated in response to high glucose and leading to abnormal expression of vascular genes.
Recently, we have identified two novel molecular pathways controlled by glucose in endothelial cells:
1. Glucose regulates the activity of Aryl Hydrocarbon Receptor (Ahr), a nuclear receptor for multiple xenobiotic compounds that has been associated with cardiovascular disease and diabetes in epidemiological studies and in animals. Ahr controls the transcription of vascular genes associated with protection from the oxidative stress, and abnormal angiogenesis and atherogenesis.
2. The pathological changes of vasculature in diabetes are tissue- and organ-specific: angiogenesis can be dramatically upregulated in one tissue/organ (retinal neovascularization) and dramatically suppressed in another tissue/organ (e.g., skin, heart). We have identified a novel tissue-specific molecular mechanism that provides explanation for the aberrant angiogenesis. Hyperglycemia upregulates the expression of miR-467 in a tissue-specific manner. miR-467 binds to the untranslated region of thrombospondin-1 (TSP-1) mRNA and inhibits TSP-1 protein synthesis. The descreased production of TSP-1, a potent anti-angiogenic protein, results in upregulation of angiogenesis in selected tissues where this mechanism is present. miR-467 is expressed in a tissue-specific manner in cancer cells and may provide an explanation for the associations of diabetes and cancer.