Vascular complications of diabetes are the main and a long-standing interest of my group. Hyperglycemia is as 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.
Despite the recent advances in treatment of diabetes, the precise control of blood glucose remains problematic. Hyperglycemia (high blood glucose) is an independent risk factor for development of vascular complications of diabetes, which are the main cause of morbidity and mortality in diabetic patients. Pathological changes of vasculature develop in most diabetic patients with type 1 and type 2 diabetes and manifest as atherosclerotic lesions in large arteries or altered vascularization of organs causing abnormal function of these organs (retinopathy, nephropathy, neuropathy, cardiomyopathy). The molecular mechanisms activated in vascular cells by high blood glucose and resulting in pathological changes of the vasculature remain largely unknown.
The intracellular molecular mechanisms that regulate vascular gene expression in response to hyperglycemia are our focus. We are examining the intracellular pathways activated by high blood glucose and controlling gene transcription and protein production and, as a result, the development of atherosclerotic lesions in large arteries and the growth of new microvessels in tissues and organs.
Extracellular matrix (ECM) undergoes the most profound changes in diabetic vasculature: the amount of ECM and its composition change dramatically. To understand the role of blood glucose in these changes, we study the pathways controlling production of thrombospondins, ECM proteins known to regulate the growth of new vessels (angiogenesis) and the development of atherosclerotic lesions.
As a result of this work, we have identified new promising potential therapeutic targets that may facilitate prevention and treatment of diabetic vascular complications and reduce the socio-economic burden of diabetes.
Stenina et al. “The increased expression of thrombospondin-1 in the vessel wall of diabetic Zucker rat” Circulation 2003.
Raman et al. “Glycosylation mediates effect of high glucose on thrombospondin-1 expression in vascular smooth muscle cells“ J. Biol. Chem. 2007
Bhattacharyya et al. “Cell-type-specific post-transcriptional regulation of production of a potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose” J. Biol. Chem. 2008
Dabir et al. “Aryl Hydrocarbon Receptor (AhR) is Activated by Glucose and Regulates the Thrombospondin-1 Gene Promoter in Endothelial Cells” Circulation Research 2008.
Raman et al. “A Novel Transcriptional Mechanism of Cell-Type-Specific Regulation of Vascular Gene Expression by Glucose” Arteriosclerosis Thrombosis and Vascular Biology 2011.
Frolova et al. “Thrombospondin-4 regulates development of early atherosclerotic lesions” Circulation Research 2010
Frolova et al. “Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload” FASEB J 2012