THE EFFECTS OF HYPOMORPHIC SIALIDASE EXPRESSION ON ATHEROSCLEROSIS

Abstract

<p>Atherosclerosis is a complex multifactorial disease which is an important risk factor for morbidity and mortality related to coronary heart disease and stroke in humans. Both lipoprotein metabolism and inflammation are related to atherosclerosis. Sialidase, a hydrolytic enzyme that is present in viruses, bacteria and vertebrates and catalyzes the removal of terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides, has impacts on the activities of many blood cells and lipoproteins. Therefore, we aim to determine the effects of hypomorphic sialidase expression on atherosclerosis. Our first objective has shown that hypomorphic sialidase expression alters lipoprotein metabolism in C57Bl/6 mice. We have dissected the mechanism showing that sialidase-deficient B6.SM mice have decreased hepatic cholesterol production via decreased microsomal triglyceride transfer protein (MTP) expression. We have further shown that a decrease in sterol regulatory element binding protein-2 (SREBP-2) expression is responsible for the decreased expression of MTP. Our second objective has shown that hypomorphic sialidase expression confers atheroprotection in <em>apoe-/-</em> mice as seen by the rescue of hypercholesterolemia cholesterol profiles and a decreased migration and infiltration of leuckocytes into atherosclerotic lesions. We have further shown that hypomorphic sialidase expression specifically in blood cells is sufficient to affect atherogenesis. Most importantly, we have discovered that treating <em>apoe-/-</em> mice with 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), a sialidase inhibitor, is a potent treatment for atherosclerosis. Our third objective has shown that hypomorphic sialidase expression confers atheroprotection via an increase in monocytic cholesterol uptake and macrophage cholesterol efflux to HDL. Taken together, hypomorphic sialidase expression is atheroprotective in C57Bl/6, ApoE-deficient and LDLR-deficient mouse models. Overall, these studies suggest that sialidase is a novel risk factor for atherosclerosis in humans and may set the stage to investigate the contribution of genetic variation within the sialidase gene to atherosclerotic cardiovascular disease in humans.</p>