Grant: Operating Grant

Following diabetes, the heart increases its lipoprotein lipase (LPL) at the coronary lumen by transferring LPL from the cardiomyocyte to the endothelial lumen. This increase in LPL can play a significant role in increasing fatty acid delivery to the heart, in addition to enhancing the development of atherosclerosis by facilitating lipoprotein uptake. We examined how hyperglycemia controls secretion of heparanase, the enzyme that cleaves myocyte HSPG (the receptor that binds LPL) to initiate this movement. Our preliminary data suggest that following hyperglycemia, translocation of LPL from the cardiomyocyte cell surface to the apical side of endothelial cells is influenced by the ability of fatty acid to increase endothelial intracellular heparanase followed by rapid secretion of this enzyme by glucose, which requires an intact microtubule and actin cytoskeleton. Given that augmented levels of heparanase activity have been reported in plasma and urine of patients with diabetic nephropathy, and overexpression of cardiac human LPL results in a cardiac phenotype resembling diabetic cardiomyopathy, we will examine the detailed mechanism that regulates heparanase synthesis and secretion following diabetes. Results from this study could help in restricting or slowing cardiac LPL translocation and could lead to strategies that overcome atherosclerosis and cardiac dysfunction following diabetes.