Biochemistry and Biomedical Sciences
Associate Professor, Medicine
Thrombosis and Atherosclerosis Research Institute
237 Barton Street East
Tel: 905 521-2100 ext 40747
My research interests are focused upon the link between diabetes mellitus and the development and progression of cardiovascular disease.
The last few decades have witnessed a dramatic, worldwide increase in the incidence of diabetes mellitus. Driven by changes in lifestyle and an escalating rate of obesity, the number of individuals with diabetes is expected to reach 300 million by the year 2025. Therefore, the diabetes epidemic is, and will continue to be, a global heath crisis. Complications associated with diabetes make it a leading cause of blindness, renal failure and lower limb amputations in adults as well as an important, independent risk factor for atherosclerotic cardiovascular disease (CVD). CVD accounts for over 65% of diabetic mortality making diabetes "a coronary heart disease risk equivalent". The treatment and prevention of diabetic complications such as CVD is currently limited by our lack of understanding of the mechanisms by which diabetes promotes CVD.
The Werstuck laboratory is located at the Henderson Research Centre, a facility dedicated to basic, clinical, and epidemiologic research in thrombosis, atherosclerosis, and cardiovascular disease. Our research is focused upon delineating the mechanisms by which diabetes mellitus promotes the progression and development of cardiovascular disease. Our laboratory employs a broad range of molecular and cellular techniques to examine cell and tissue-specific responses to hyperglycemia, obesity and diabetes.
Current areas of investigation in the Werstuck lab include:
Examining the intracellular effects of hyperglycemia
This research involves the treatment of cell types relevant to the development of atherosclerosis including; human aortic smooth muscle cells, endothelial cells, monocytes and macrophages with elevated concentrations of glucose and glucose metabolites. Genomic and proteomic techniques are utilized to identify specific changes in gene expression. The lab is particularly interested in the role of glutamine-fructose amidotransferase (GFAT), the rate-limiting enzyme involved in the conversion of glucose to glucosamine. Our findings suggest that this enzyme may play a central role in the development of complications associated with diabetes mellitus.
Identification of molecular targets for therapeutic intervention
The work described above has lead to the identification of pathways that can potentially be targeted in order to attenuate the downstream complications of diabetes/hyperglycemia including CVD. In collaboration with an organic chemistry laboratory, we are designing, synthesizing and testing novel inhibitors of intracellular targets in our cell culture systems. The most promising compounds will be tested in established animal models of diabetes mellitus to assess their anti-atherogenic potential.
Examining samples from human patients
In order to test the relevance of pathways and mechanisms that have been identified in our cell culture and animal models of diabetes mellitus we have formed collaborations with clinicians who have access to patients with diabetes and CVD. Protein and nucleic acid are purified from blood samples from these patients. Specific markers of interest are quantified relative to samples from non-diabetic controls and compared to data collected from our models systems.
- McAlpine C, Huang A, Emdin A, Banko N, Beriault D, Shi Y, Werstuck G (2015) Deletion of myeloid GSK3α attenuates atherosclerosis and promotes an M2 macrophage phenotype. Arterioscler Thromb Vasc Biol 35, 1113-1122.
- McAlpine CS, Werstuck GH (2014) PKR-like Endoplasmic Reticulum Kinase (PERK) signals through Glycogen Synthase Kinase (GSK)-3α/β to regulate Endoplasmic Reticulum (ER) stress-induced foam cell formation. J Lipid Res 55, 2320-2333
- Banko N, McAlpine CS, Venegas-Pino DE, Raja P, Shi Y, Khan MI, Werstuck GH (2014) Glycogen Synthase Kinase 3 alpha deficiency protects LDLR knockout mice from high fat diet induced accelerated atherosclerosis. Am J Pathol 184, 3394-3404
- Gerstein HC, Werstuck GH (2013) Vasculopenia and the Chronic Consequences of Diabetes. The Lancet Diabetes & Endocrinology 1, 71-78
- Venegas-Pino DE, Banko N, Khan MI, Shi, Y, Werstuck GH (2013) Quantitative Analysis and Characterization of Atherosclerotic Lesions in Mice. J of Visualized Experiments (82) 50933
- Veerman KJ, Venegas-Pino DE, Khan MI, Shi Y, Gerstein HC, Werstuck GH (2013) Hyperglycaemia is Associated with Impaired Vasa Vasorum Neovascularisation and Accelerated Atherosclerosis in Apolipoprotein-E Deficient Mice. Atherosclerosis 227, 250-258
- McAlpine C, Bowes AJ, Khan MI, Shi YY, Werstuck GH (2012) Endoplasmic reticulum stress and glycogen synthase kinase-3b activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 32, 82-91.
- Sage AT, Ottenhof SH, Shi YY, Danjanovic S, Sharma AM, Werstuck GH (2012) Metabolic syndrome and acute hyperglycemia are associated with endoplasmic reticulum stress in human mononuclear cells. Obesity 20, 748-755.
- Beriault DR, Sharma S, Shi Y, Khan MI, Werstuck GH (2011) Glucosamine-supplementation promotes endoplasmic reticulum stress, hepatic steatosis and accelerated atherogenesis in apoE-deficient mice. Atherosclerosis 219, 134-140.
- Sage AT, Walter LA, Shi YY, Khan MI, Kaneto H, Capretta A, Werstuck GH (2010) Hexosamine biosynthesis pathway (HBP) flux promotes endoplasmic reticulum (ER) stress, lipid accumulation, and inflammatory gene expression in hepatic cells. Am J Physiol Endocrinol Metab 298, E499-E511.