HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

Abstract

The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexible collar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 ing/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36±0.04 versus 0.03±0.02). Animals treated with lovastatin (R=12), simvastatin (n=12), and fluvastatin (R=12) showed significantly less neointimal formation; I/M tissue ratios were 0.24±0.03, 0.20±0.03, and 0.17±0.03, respectively. The inhibition elicited by pravastatin (n=12, 032 ±0.03) did not reach statistical significance. or-Actin antibody immunofluorescence analysis of serial sections revealed that cells present in the hyperplastic intima were mostly myocytes. Rates of intimal myocyte proliferation were also measured by incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into replicating DNA. Immunofluorescence analysis showed that 5-bromo-2'-deoxyuridine was actively incorporated into intimal myocytes after insertion of the collar, with a labeling index (percent of labeled myocytes) of 2.15 after 14 days. Labeling indexes for pravastatin-, lovastatin-, simvastatin-, and fluvastatin-treated carotid arteries were 2.01, 1.32,1.23, and 1.20, respectively, suggesting a direct effect of vastatins on arterial myocyte proliferation. The different responsiveness shown by the vastatins tested may be attributed to the differences in their capacity to penetrate cell membranes and their potency in inhibiting the HMG CoA reductase enzyme. We conclude that the inhibition of carotid intimal myocyte proliferation by these vastatins is independent of their effect on plasma cholesterol concentrations. -11 suggesting that the hypolipidemic effect is

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

“…In a similar study using¯uvastatin sodium, another HMGCoA reductase, while the per cent areas of smooth muscle cells, collagen ®bres, and extracellular lipid deposits were decreased, the per cent area of macrophages was increased in the early atherosclerotic lesions of young WHHL rabbits (Shiomi et al, 1998). Both cerivastatin and¯uvastatin show inhibitory e ects on proliferation of smooth muscle cells in in vitro studies (Corsini et al, 1996;Negre-Aminou et al, 1997;Bellosta et al, 1998) and in vivo studies using normocholesterolaemic rabbits which had neointimal thickening of arteries caused by injury (Soma et al, 1993;Bandoh et al, 1996;Igarashi et al, 1997b). However, in our studies using young WHHL rabbits, uvastatin caused a decrease in the per cent area of smooth muscle cells in the atherosclerotic lesions whereas cerivastatin did not, despite the similar hypolipidemic e ects of the two drugs.…”

“…However, in our studies using young WHHL rabbits, uvastatin caused a decrease in the per cent area of smooth muscle cells in the atherosclerotic lesions whereas cerivastatin did not, despite the similar hypolipidemic e ects of the two drugs. On the other hand, pravastatin, which shows little inhibitory e ect on smooth muscle cell proliferation in vitro (Soma et al, 1993;Corsini et al, 1996;Bellosta et al, 1998) decreased the per cent area of macrophages and extracellular lipid deposits, but did not a ect smooth muscle cells in the established lesions of mature WHHL rabbits (Shiomi et al, 1995). These results suggest that the e ects of various HMGCoA reductase inhibitors on the composition of atherosclerotic lesions di er, despite the similar hypolipidemic e ects.…”

Overexpression of Truncated IκBα Induces TNF-α–Dependent Apoptosis in Human Vascular Smooth Muscle Cells

“…Thus, the induction of VSMC apoptosis may act concurrently with the inhibition of cell proliferation in preventing neointima formation, as has been proposed in studies with experimental models. 36 Erl et al 37 reported that inhibition of NF-B by adenovirus-mediated overexpression of I B␣ caused a marked increase in cell death at a low cell density but not at a high cell density. Therefore, overexpression of I B⌬N may reduce excessive VSMC proliferation and have therapeutic value in inhibiting neointima formation after angioplasty and arterial injury.…”

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

“…12,14 Statins can suppress endothelial and vascular smooth muscle cell inflammatory and proliferative responses to injury. [15][16][17] These effects involve inhibition of isoprenylation of rho-and rac-family GTPases that couple growth factor receptors to the intracellular MAP/ERK kinase signaling pathways and induction of the cell cycle inhibitor p27…”