Cardiovascular Disease, Endothelial Cell Gene Expression, and Renal Dysfunction in Insulin Resistant, Hyperlipidemic Swine

Globally, the prevalence of insulin resistant (IR), type-2 diabetes mellitus (DM) is increasing. Both IR and DM are associated with an increase in cardiovascular events and renal pathology. The underlying cause for this increase is, as yet, not completely understood. A thoroughly characterized model is needed to identify mechanisms connecting insulin resistance with cardiovascular and renal disease. Through selective breeding we have produced hyperinsulinemic pigs that develop hypercholesterolemia when fed a high fat diet. A subgroup of these pigs develops severe and diffuse proximal and distal abdominal aorta and coronary artery atherosclerosis compared to the other group which has moderate disease. Through aortic endothelial cell gene expression studies we have identified three genes (MERP-1, RABGAP1L, COL12A1) that are uniquely expressed in the atherosclerotic endothelium of the severe disease group. Additionally, a subgroup of the pigs develops renal histopathology that mirrors the phenotype of an insulin resistant/diabetic nephropathy when albuminuria is present. All pigs have been monitored over the course of one year on a high fat, high sodium diet for weight, backfat, blood pressure, insulin sensitivity, total and LDL cholesterol, triglycerides, oxidized LDL, fructosamine, inflammatory makers, and aldosterone. The goals of this proposal were to characterize this pig model with regards to 1- presence and severity of coronary and aortic atherosclerosis and its association with markers of oxidative stress, 2-changes in endothelial cell gene expression as it relates to the severity of aortic atherosclerosis, and 3-extent of renal pathology and its resemblance to human diabetic renal disease. This will support the long range goal of this laboratory, which is to provide the scientific community with a well-characterized, useful animal model of insulin resistance and/or type-2 diabetes, which develops human-like coronary and aortic atherosclerosis and IR/diabetic like nephropathy