HYPERCHOLESTEROLEMIA ALTERS THE GENE-EXPRESSION OF NOVEL COMPONENTS OF THE EXTRACELLULAR-MATRIX IN EXPERIMENTAL VEIN GRAFTS

The success rate of vascular bypass procedures is limited by the devel opment of intimal hyperplasia (IH). Hypercholesterolemia has been show n to accelerate IH in both arteries and experimental vein grafts; howe ver the mechanism remains uncertain. Hyaluronic acid synthase (HAS-1) is a transmembrane enzyme responsible for the formation of hyaluronan; an important constituent of extracellular matrix (ECM). The integrin receptor for hyaluronan is CD-44. Both CD-44 and HAS-1 have been studi ed in the development of ECM of wounds but have yet to be examined in the ECM of IH within vein grafts. The purpose of this study was to det ermine if the expression of CD-44 and HAS-1 is increased during the ea rly stages of IH and how cholesterol supplementation affects these gen es. Forty white male New Zealand rabbits were divided into two groups: cholesterol supplemented (1% cholesterol chow) and noncholesterol sup plemented. Each set of 20 rabbits was then divided into four additiona l groups (n = 5); a nonoperative group (control) and three operative g roups that underwent a right interposition carotid bypass using jugula r vein. Grafts were harvested at 3, 7, and 21 days after surgery for m olecular studies and histology. Ribonuclease protection assays were pe rformed using P-32-labeled riboprobes for HAS-1, CD-44, and 18s rRNA. Densitometric analysis is expressed as a ratio (riboprobe/rRNA). Chole sterol levels differed significantly between cholesterol supplemented and nonsupplemented groups (1419 +/- 130 mg/dl and 48 +/- 12 mg/dl) (p < 0.01). There was a significant increase in the expression of HAS-1 and CD-44 in the vein grafts compared to normal jugular vein. Choleste rol supplementation caused a further increase in CD-44 gene expression versus nonsupplemented vein grafts. These data demonstrate a role for CD-44 and HAS-1 transcription in vein graft intimal hyperplasia, whic h is further altered by cholesterol supplementation. Lastly, these res ults could explain differences seen in the development of IH with hype rcholesterolemia and ultimately provide for improved therapies in alle viating this process.