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We developed a rat double-balloon injury model and studied the thickened neointima using immunohistochemical and RT-PCR methods. Fourteen days after the first balloon injury of the rat left common carotid artery, a second balloon injury was inflicted in the same place. Histochemical sections taken 14 days after the single- and double-balloon injuries were used for calculating intimal/medial (I/M) area ratios, as an indicator of neointimal formation, and were subjected to immunohistochemical staining. Total RNA was also purified from some arteries and mRNA expression of some extracellular matrices (ECM) and cytokine receptors related to ECM metabolism was estimated using the RT-PCR method. The I/M ratio in the rat double-balloon injury model (II) (1.84±0.62 (mean±SE, n=5)) was significantly (p<0.05) higher than that in the single-balloon injury model (I) (1.30±0.19, n=10). The cell number per neointimal area was less in II than in I. As for the phenotype of smooth muscle cells, α-actin staining showed that the neointima of II consisted of more contractile form than synthetic, whereas that of I consisted of more synthetic form than contractile. The neointima of II was strongly stained with laminin and fibronectin, but that of I was stained only weakly. Consistent with these data, laminin and fibronectin mRNAs were markedly expressed in the neointima of II. Neointimas of both I and II were also stained positively with PDGF (α and β) and TGF-β (types I and II) receptors to the same extent. These results show: that ECM accumulation, particularly of laminin and fibronectin, characterizes the double-balloon injury model; that the marked accumulation of ECM in this model is due to a mechanism other than the PDGF or TGF-β signalling pathway; and that this model resembles the lesion of post-PTCA re-stenosis, and therefore provides the key for its investigation. [ABSTRACT FROM AUTHOR]

In order to test whether a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor has an anti-atherogenic activity, the effects of carvastatin, a newly developed potent inhibitor, and pravastatin were examined on the intimal thickening of the artery after the endothelial denudation induced by balloon catheter injury. Rabbits were divided into four groups; control, pravastatin-treated (20 mg kg[sup -1] day[sup -1]) and two of carvastatin-treated groups (10 or 20 mg kg[sup -1] day[sup -1]). Two weeks after balloon catheter injury, the areas of intima and media of the injured carotid arteries were determined, and the ratios of intima to media (I/M) were calculated as an index of intimal thickening. Average I/M ratios of the injured artery were 0.42±0.05 for control, 0.49±0.07 for pravastatin, 0.19±0.03 (10 mg kg[sup -1] day[sup -1]) and 0.20±0.04 (20 mg kg[sup -1] day[sup -1]) for carvastatin-treated rabbits, respectively. Thus, carvastatin reduced I/M ratio of the injured artery to approximately half versus control, but pravastatin failed to suppress the intimal thickening. For in vitro study, vascular smooth muscle cells (SMC) from rabbit aorta were explanted, then cultured, and the effects of carvastatin on SMC migration and SMC proliferation were also examined. Carvastatin inhibited dose-dependently SMC migration and SMC proliferation with IC[sub 50] values of 0.5 μM and 1 μM, respectively. These inhibitory effects of carvastatin were cancelled by the coexistence of mevalonate, a metabolite of cholesterol synthesis. Our results suggest that carvastatin may be useful in rabbits as an anti-atherogenic drug by means of the inhibition of SMC migaration or SMC proliferation. [ABSTRACT FROM AUTHOR]

The role of sialic acid linked with lipoprotein lipase (LPL) in its catalytic activity was studied. When LPL was treated with sialidase, the molecular weight decreased by 2000. The sialidase-treated LPL showed unchanged hydrolyzing activity for tributyrin, a water-soluble substrate of esterase, compared with the untreated LPL. The sialidase-treated LPL also showed similar hydrolyzing activity for triolein emulsified with Triton X-100, phosphatidylcholine and phosphatidylethanolamine, whereas it showed significantly increased hydrolyzing activity for triolein emulsified with phosphatidylserine and cardiolipin (152% and 183%, compared with untreated LPL, respectively). In addition, the sialidase-treated LPL showed significantly increased hydrolyzing activity against triolein incorporated into very low-density lipoproteins and chylomicrons (151% and 186% compared with the untreated LPL, respectively). These results suggest that the loss of sialic acids does not modify the function of the catalytic site of LPL, but facilitates the interaction of the enzyme with the interface of the surface of substrate lipoproteins. [ABSTRACT FROM AUTHOR]

Effects of fatty acids on intimal thickening induced by a balloon catheter injury model were investigated by feeding rabbits a small amount of either lard [L] or fish oil [F]. Serum lipids of these groups were not different from those of basal diet - fed rabbits [controls] after 4 weeks of feeding. Serum saturated fatty acids such as 14 : 0, 16 : 0, and 18 : 0 were significantly greater in the L - fed rabbits compared with controls, but those of the aorta were not significantly different. Fatty acid composition of the F - fed rabbits was only different from that of the controls in that n - 3 fatty acids slightly increased. The mean and maximum intimal thickenings 2 weeks after ballooning, carried out 2 weeks after feeding, were significantly higher in the carotid arteries of the L - fed rabbits than in the controls. The intimal thickening of the F - fed rabbits did not significantly differ from that of the controls. These results suggest that lard promotes the formation of the smooth muscle cell dominant type of arteriosclerosis without affecting serum lipid levels. [ABSTRACT FROM AUTHOR]