Inhibitory effect of fluvastatin on aortic intimal thickening in normocholesterolemic rabbits

The anti-atherosclerotic effect of fluvastatin at does insufficient to lower serum cholesterol on the catheter-induced intimal thickering and possible mechanism were investigated in abdominal aorta of rabbits.

Fifty-six rabbits were randomly divided into eight groups (n = 7, each). Fluvastatin was given mixed with food at daily dose of 8 mg/kg starting 5 days before catheterization. Light microscope, immunohistochemistry, transmission electron microscope and RT-PCR assay were applied to assess vascular smooth muscle cell (VSMC) proliferation and apoptosis, as well as oncogene expression in vascular wall.

At day 10 and day 15 after catheter induced denudation intima/media (I/M) thickness ratio was obviously higher, and also the percentage of PCNA-positive cells and TUNEL-positive cells in media was significantly higher compared with controls. The intimal hyperplasia was mostly composed of alpha-SM-actin-positive cells. In rabbits given fluvastatin I/M ratio and the percentage of these positive cells significantly decreased compared with those without fluvastatin. The overexpression of proto-oncogene H-ras mRNA and decreased expression of anti-oncogene p53 mRNA were found after vascular injury, whereas fluvastatin significantly reduced H-ras mRNA and increased p53 mRNA expression.

Proliferation of VSMC in the media and the migration to the intima can be inhibited, and apoptosis of VSMC be induced by short-term use of fluvastatin after balloon catheter denudation, independent of serum lipid change. The underlying mechanism is presumably associated with the influence of fluvastatin on oncogene expression in the injured vascular wall.