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Doctor of Philosophy (PhD)




Diabetes leads to several alterations in cardiac structure, one of which is fibrosis of the ventricular myocardium. Myocardial fibrosis is a common underlying factor in most cardiac pathologies. Osteopontin (OPN) is a small phospho-protein that has been implicated in fibrotic tissue remodeling. In the heart, the expression of OPN protein is increased after acute and chronic pathologies. Upregulation of OPN coincides with a transition to heart failure and a direct role for OPN in the progression of diabetic cardiomyopathy to heart failure has been reported.

The overall objective of this project is to determine if OPN is upregulated in the heart in a model of type 2 diabetes and if OPN is increased in cardiac cells in response to high glucose. The hypotheses of the project are that OPN expression is increased in the type 2 diabetic heart, cardiac cells contribute to the increased OPN expression in the heart, and high glucose increases OPN expression in cardiac cells. Our proposed pathway of high glucose induced OPN expression is mediated by Angiotensin II (Ang II) and protein kinase C (PKC).

In this study I use a type 2 diabetic rat model to determine if OPN expression is increased in the LV. Isolated neonatal rat ventricular myocytes and fibroblasts were used to determine upregulation of high glucose in cardiac cells and to elucidate the regulation of OPN expression in response to high glucose by Ang II and PKC. My results show that OPN expression is increased in the LV of a model of type 2 diabetes. Further I determined that both myocytes and fibroblasts increase OPN expression in response to high glucose. Inhibition of Ang II receptors and production decreased OPN expression in response to high glucose. To determine PKC regulation of OPN expression general and classical PKC inhibitors were used, both of which inhibited increased OPN expression in response to high glucose. A role for PKC in OPN expression was determined by overexpressing constitutively active and dominant negative recombinant PKC proteins. These results provide a better understanding of the signal transduction pathways leading to the cardiac dysfunction seen in diabetic patients.

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