Inhibitory Effect Of Fluvastatin Research Articles

Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery

The anti-atherosclerotic effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors at doses insufficient to lower serum cholesterol was investigated in rabbit femoral artery denuded by balloon catheter. Fluvastatin and pravastatin were given orally at doses of 4 and 8 mg/kg per day, respectively, for 2 weeks after the catheterization. There was little change in serum cholesterol, triglyceride and phospholipid by chronic treatment with the drugs. The cross-sectional area of the intima, expressed as relative values to media ( I M ratio), was increased by the catheterization, showing intimal thickening in the denuded arteries. The I M ratio was reduced by fluvastatin but not pravastatin: 0.327 ± 0.060 for control, 0.116 ± 0.035 for 4 mg/kg fluvastatin, 0.088 ± 0.027 for 8 mg/kg fluvastatin and 0.22 ± 0.069 for 8 mg/kg pravastatin. Fluvastatin (8 mg/kg)-induced effect on the I M ratio, was prevented by the combined administration with 40 mg/kg per day mevalonate, a metabolite in the HMG-CoA reductase pathway. These results suggest that fluvastatin inhibits intimal thickening after catheterization-induced injury through percutaneous transluminal coronary angioplasty (PTCA) and that the inhibition is presumably attributed to reduced migration and proliferation of smooth muscle cells but not secondarily to a lowering of serum lipid.

Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits.

1. The effects of fluvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the vascular angiotensin converting enzyme (ACE) activity in hyperlipidaemic rabbits were compared with those of enalapril, an ACE inhibitor. 2. Rabbits were fed a 1.5% cholesterol containing diet or normal diet for 16 weeks and treated with either fluvastatin or enalapril in the diet at the respective doses of 2 and 10 mg kg-1 day-1. The total cholesterol, triglyceride and phospholipid levels in serum were significantly increased in rabbits fed the high cholesterol diet. Treatment with fluvastatin but not enalapril resulted in a decrease in serum lipids. 3. The vascular ACE activities assessed via the cleavage rate from synthetic substrate in the aortic arches and upper thoracic aortae were increased by 8 to 10 times when the rabbits were made hyperlipidaemic. Fluvastatin as well as enalapril significantly lowered the tissue ACE in the aortae. 4. The ACE activities in serum did not alter in hyperlipidaemic rabbits either in the presence or absence of fluvastatin. The serum ACE activity was lowered by enalapril. 5. The lipid peroxide in serum as well as the plaque area in the thoracic aorta was significantly increased in the cholesterol diet-fed rabbits. Treatment with fluvastatin or enalapril reduced both serum lipid peroxide and plaque formation. The relaxant responses to acetylcoholine (ACh) were significantly suppressed in the cholesterol-fed rabbits. Treatment with fluvastatin or enalapril significantly reversed the suppression of ACh-induced relaxation. 6. It seems that the reduction of vascular ACE is not coupled to lipids and ACE activity in serum, but rather to lipid peroxidation. Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression in the vasculature.

P-985 - The inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line.

P-985 - The inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line.

HMG-CoA Reductase Inhibitors Reduce Acetyl LDL Endocytosis in Mouse Peritoneal Macrophages

We previously reported that mevalonate starvation elicited by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced cholesterol accumulation promoted in murine macrophages by acetylated LDL (AcLDL). In the present study we investigated the cellular mechanism of this effect. Our results indicate that the HMG-CoA reductase inhibitors fluvastatin and simvastatin reduce, in a concentration-dependent manner, more than 50% of the 125I-AcLDL degradation by macrophages. This effect was not due to a decrease of lysosomal enzyme activity, and it was paralleled by the retention of AcLDL-associated cholesteryl ester in the incubation medium. The ability of fluvastatin to inhibit AcLDL degradation was completely overcome by mevalonate and its derivative geranylgeraniol. Evaluation at 4 degrees C of 125I-AcLDL binding to plasma membrane suggested that the inhibitory effect of fluvastatin on lipoprotein catabolism was not due to a decreased expression of scavenger receptors. Fluorescent microscope analysis of cellular internalization of AcLDL labeled with the fluorochrome 3,3'-dioctadecyl indocarbocyanine demonstrated that fluvastatin inhibits lipoprotein endocytosis, an effect reversed by mevalonate. Studies performed with native 125I-LDL indicated that fluvastatin did not inhibit but rather increased the degradation of LDL taken up by the normal LDL receptor. These results exclude a generalized depression of the cellular endocytotic activity by the drug. The ability of fluvastatin to reduce AcLDL catabolism and cholesterol esterification was more pronounced in cholesterol-enriched macrophages compared with normal cells. In conclusion, the present results demonstrate that HMG-CoA reductase inhibitors may reduce the in vitro cholesterol accumulation in macrophages by inhibiting AcLDL endocytosis.

Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention. in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis—and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70–90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70–80%) by famesol or geronylgeraniol. This confirms the specific role of isoprenoid metabolites—most probably geronylgerylated protein(s)—in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. Taken together, these data support the importance of pharmacologic modulation of the mevalonate pathway in controlling major events involved in atherogenesis.

Pathogenesis of atherosclerosisand the role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention. in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis—and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70–90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70–80%) by famesol or geronylgeraniol. This confirms the specific role of isoprenoid metabolites—most probably geronylgerylated protein(s)—in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. Taken together, these data support the importance of pharmacologic modulation of the mevalonate pathway in controlling major events involved in atherogenesis.

Characterization of the hyperpolarizing-activated current (I f) in human atrial myocytes

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention. in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis—and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70–90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70–80%) by famesol or geronylgeraniol. This confirms the specific role of isoprenoid metabolites—most probably geronylgerylated protein(s)—in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. Taken together, these data support the importance of pharmacologic modulation of the mevalonate pathway in controlling major events involved in atherogenesis.

Mevalonate is essential for growth of porcine and human vascular smooth muscle cells in vitro.

The effects of mevalonate depletion on growth and cell cycle kinetics of porcine and human vascular smooth muscle cells (SMC) were studied by growth curves and flow cytometric determination of cell cycle distribution. Porcine and human SMC were growth arrested by serum depletion for 48 h. Subsequently, they were stimulated to maximal growth and DNA synthesis by addition of serum. There was a concentration dependent decrease in the proliferation of human and porcine SMC, when cells were incubated in the presence of fluvastatin, a new, fully synthetic HMGCoA-reductase inhibitor. The reduction of cell number was significant with 10(-5) M and 10(-4)M fluvastatin. The highest concentration induced cell loss after prolonged incubation (> 4 days). The G/S-phase transition of human and porcine vascular SMC was reduced to 50% of controls by 10(-4) M fluvastatin as revealed by cell cycle analysis. The effects of fluvastatin on growth kinetics and cell cycle distribution could be completely reversed by the addition of 1 mM mevalonolactone. This indicates that the inhibitory effect of fluvastatin is caused by the inhibition of HMGCoA-reductase and depletion of mevalonate rather than being unspecific. Addition of LDL to supply cholesterol failed to support cell growth and transition of smooth muscle cells from G(zero)/G1-phase to S-phase, even though LDL was taken up by the cells as shown by confocal fluorescence microscopy. Neither did the addition of squalene or cholesterol to the culture medium normalize cell growth. It is concluded that nonsterol products that are synthesized from mevalonate are necessary for growth of smooth muscle cells. HMGCoA-reductase inhibitors like fluvastatin block the synthesis of these nonsterol precursors in human and porcine vascular SMC in vitro and are therefore growth inhibitory.

The hyperpolarization-activated current, I F, is expressed in rat hypertrophied ventricular myocytes

Atherosclerosis is a complex multifactorial process resulting from an excessive inflammatory/fibroproliferative response to various forms of injurious stimuli to the arterial wall. The potential interactions of cells, cytokines, and growth-regulatory molecules among the different cells in the atherosclerotic lesion present numerous opportunities for modulating lesion formation and progression. Smooth muscle cell (SMC) migration and proliferation, together with lipid deposition, are now recognized as the major phenomena occurring within the arterial wall, and thus these phenomena serve as targets for pharmacologic intervention. in the process of atherogenesis. Migration and proliferation of SMC are key events in atherosclerosis—and in restenosis after angioplasty. An understanding of the factors that induce such events is important for the prevention and treatment of these diseases. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell proliferation; hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, this group provided in vitro and in vivo evidence of decreases in SMC proliferation by fluvastatin and simvastatin, but not pravastatin, independent of their cholesterol-lowering properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70–90% decrease) was completely prevented by the addition of mevalonate, and partially prevented (70–80%) by famesol or geronylgeraniol. This confirms the specific role of isoprenoid metabolites—most probably geronylgerylated protein(s)—in regulating cell migration and proliferation. The inhibitory effect of fluvastatin and simvastatin on cholesterol esterification induced by acetyl low density lipoprotein in macrophages was also prevented by the addition of geranylgeraniol. Taken together, these data support the importance of pharmacologic modulation of the mevalonate pathway in controlling major events involved in atherogenesis.

Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages

HMG-CoA reductase inhibitors simvastatin, fluvastatin and fluvastatin enantiomers (0.1 to 5 μM) were utilized to block both mevalonate formation and cholesterol esterification in mouse peritoneal macrophages in the presence of a large excess of cholesterol supplied by acetylated LDL. Supplementation of cultures with mevalonate fully reversed, in a dose-dependent manner, the inhibitory effect of the drugs on cholesterol esterification. Mevalonate alone, in the range of the tested concentrations, did not affect cholesterol esterification in the absence of the HMG-CoA reductase inhibitors, indicating that its effect was linked to the restoration of the endogenous pool depleted by the pharmacological block of HMG-CoA reductase. The inhibitory effect of fluvastatin was also prevented by the non-sterol mevalonate isoprenoid derivative geranylgeraniol. Evaluation of fluvastatin enantiomers demonstrated the stereo-specificity of drug action with most of the effect associated to the antipode with the highest inhibitory activity of HMGCoA reductase. We conclude that mevalonate or a mevalonate product(s), possibly a non-sterol derivative(s), are required in cholesterol esterification induced by acetylated LDL in macrophages.