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

Abstract

1 The aim of this study was to examine whether cerivastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a ects the lesional composition of spontaneously developed atherosclerosis due to hypercholesterolaemia and delays progression of the lesions. 2 We administered cerivastatin to 2-month-old WHHL rabbits, a low-density lipoprotein receptorde®cient animal model, at a dose of 0.6 mg kg 71 day 71 for 32 weeks. We examined the plasma lipid levels, the severity of atherosclerosis, and composition of atherosclerotic lesions. Lesional composition was determined using immunohistostaining for macrophages and smooth muscle cells, and Azan-Mallory staining for collagen ®bres and extracellular lipid deposits. 3 Compared to the control group, the plasma cholesterol levels were decreased in the treated group by 39% (12.7+0.6 mmol L 71 versus 20.9+1.0 mmol L 71 , P50.001). Atherosclerosis was suppressed by about 37% as measured by the thickness of the aortic lesions (158+13 mm versus 250+15 mm, P50.001), and by 28% as measured by coronary stenosis (62.7+11.4 versus 86.9+12.2, P50.05). In the cerivastatin group, regarding the per cent areas of lesional components in the lesion area, the macrophages (21.0+1.5% versus 27.9+1.9%, P50.01) and extracellular lipid deposits (3.2+0.4% versus 5.1+0.4%, P50.001) were decreased in the aortic lesions, and the per cent area of macrophages in the coronary lesions was also decreased (4.9+1.4% versus, 11.6+2.4%, P50.05). The per cent area of smooth muscle cells and collagen ®bres did not signi®cantly decrease. 4 These results indicate that cerivastatin contributed to the plaque stabilization and delayed progression of early atherosclerosis in young WHHL rabbits, in addition to the potent hypolipidemic e ects.

Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages

“…41 They are also in the range of concentrations found to be effective in previous studies in rabbits. 42,44 The dose-related effects of the other statins were obtained at 100-fold higher concentrations, consistent with their known potencies against HMG-CoA reductase and the higher clinical doses 10 to 80 mg/d. 43,45 The concentrations of statins used in our experiments were consistent with those found to cause other non-lipid-lowering effects.…”

“…Secretion of all 3 MMPs was decreased 52Ϯ19%, 71Ϯ18%, and 73Ϯ17%, respectively (PϽ0.01, nϭ3) by 50 nmol/L cerivastatin, a plasma concentration previously shown to be associated with cholesterol-lowering effects in vivo. 41,42 Lov-astatin at a concentration of 5 mol/L also inhibited IL-␣ and PDGFBB-stimulated MMP-1, -3, and -9 secretion by 94Ϯ5%, 78Ϯ24%, and 74Ϯ9.8%, respectively (PϽ0.01, nϭ3) ( Figure I, available online at http://atvb.ahajournals. org), consistent with the relative potencies of cerivastatin and lovastatin as HMGCoA reductase inhibitors.…”

Does Therapeutic Intervention Achieve Slowing of Progression or Bona Fide Regression of Atherosclerotic Lesions?

“…12 The WHHL rabbit, an LDL-receptor-deficient model of atherosclerosis that develops aortic lesions on a chow diet, was used in the past decade to study the effects of drug intervention. 13 Thus, statins were shown to reduce plasma cholesterol levels and to decrease the progression of atherosclerosis, but even after 8 months, they did not cause the regression of established lesions; this was also true in less recent studies (see Discussion in Shiomi and Ito 13 ).…”

Inflammation and Atherosclerosis

“…Both experimental and clinical outcome data now support the hypothesis that statins, in addition to being potent LDL-lowering agents, also attenuate plaque inflammation and influence plaque stability. Both pravastatin and cerivastatin can reduce macrophage content within experimental atherosclerotic plaques, [83][84][85] whereas simvastatin, fluvastatin, and atorvastatin appear to reduce intimal inflammation 86 and suppress the expression of tissue factor and matrix metalloproteinases both in vivo and in vitro. 87,88 Statins may also inhibit expression of adhesion molecules critical for monocyte attachment and adhesion to the vascular endothelium.…”