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R Fumagalli

Publications and source records attributed to R Fumagalli.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation.

The mevalonate (MVA) pathway is involved in cell proliferation. We investigated drugs acting at different enzymatic steps on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (0.1-10 microM) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 microM MVA, 10 microM all-trans farnesol (F-OH) and 5 microM all-trans geranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of cell proliferation was possible by all-trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 microM), a potent squalene synthase inhibitor, blocked cholesterol synthesis and slightly inhibited (21% decrease) SMC proliferation only at the highest tested concentration. NB-598 (1-10 microM), a potent squalene epoxidase inhibitor, blocked cholesterol synthesis without affecting SMC proliferation. Finally, the benzodiazepine peptidomimetic BZA-5B (10-100 microM), a specific inhibitor of protein farnesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was prevented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC proliferation was not affected by the closely related compound BZA-7B, which does not inhibit protein farnesyltransferase. Altogether, these findings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins, in the control of this cellular event.

Animals↗
PubMed1997

[Pharmacological control of biosynthesis pathway of mevalonate: effect on the proliferation of arterial smooth muscle cells].

The role of mevalonic acid (MVA) and its products (isoprenoids) in cell proliferation prompted us to investigate the effect of drugs affecting diverse enzymatic steps of the MVA pathway on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of HMG-CoA reductase (statins) decreased SMC proliferation in a dose-dependent manner. The inhibitory effect induced by simvastatin 3.5 microM (70% +/- 3.8 decrease) was prevented by addition of 100 microM MVA, (100% +/- 2.3), 10 microM farnesol (F-OH) (85% +/- 1.2) and 5 microM of all-trans geranylgeraniol (GG-OH) (precursor of prenylated proteins) (81% +/- 1.1), but not by 2-cis GG-OH (precursor of dolichols), squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-PP decarboxylase. Squalestatin 1 (1-25 microM) and NB-598 (1-10 microM), potent squalene synthase and epoxidase inhibitors, respectively, caused a complete inhibition of cholesterol synthesis without affecting SMC proliferation. Finally, BZA-5B (10-50 microM) a specific inhibitor of protein farnesyl tranferase (PFTase), inhibited SMC proliferation in a dose- (10-50 microM) and time-dependent manner, reaching 52% +/- 6.3 inhibition after 9 days, in the presence of 50 microM BZA-5B, without affecting cholesterol synthesis. This effect was partially prevented by mevalonate (76% +/- 3.2) and GG-OH (87% +/- 7.3) but not by F-OH. On the other hand, SMC proliferation was not affected by the closely related compound BZA-7B (93% +/- 4), which does not inhibit PFTase. Taken together, these findings support the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins in cell proliferation.

Animals↗
PubMed1996

Effect of the new HMG-CoA reductase inhibitor cerivastatin (BAY W 6228)on migration, proliferation and cholesterol synthesis in arterial myocytes.

The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC50 values of 2.7 microM and 0.5 microM, respectively. Among the tested statins BAY W 6228 resulted to be the most potent inhibitor of cholesterol synthesis and cell proliferation. Conditions producing 80-90% inhibition of cholesterol synthesis correlate with approximately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitro inhibition of cell migration and proliferation induced by BAY W 6228 (80% decrease) was completely prevented by the addition of mevalonate and partially prevented (60-80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in regulating these cellular events. The present results provide evidence that BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis.

Animals↗
PubMed1996

Relief of hypoxemia contributes to a reduction in cardiac index related to the use of positive end-expiratory pressure.

OBJECTIVE: We have investigated the role that improvement in arterial oxygenation has, consequent on positive end-expiratory pressure (PEEP), in the reduction of cardiac index (CI) determined by applying PEEP. DESIGN: 2 x 2 factorial trial. SETTING: Department of intensive care medicine at a university hospital. PATIENTS: 13 patients on mechanical ventilation for acute lung injury. INTERVENTIONS: Four experimental conditions, each one characterized by one level of PEEP and one level of PaO2: LOLP = Low PaO2 (approximately 50 mmHg) Low PEEP (approximately 1 cmH2O) LOHP = Low PaO2 (approximately 50 mm Hg) High PEEP (approximately 10 cmH2O) HOLP = High PaO2 (approximately 80 mmHg) Low PEEP (approximately 1 cmH2O) HOHP = High PaO2 (approximately 80 mmHg) High PEEP (approximately 10 cmH2O) MEASUREMENTS AND RESULTS: Hemodynamic and gas exchange data were collected for each experimental condition. CI showed a 13% decline from LOLP (7.0 +/- 1.71/min per m2) to HOHP (6.1 +/- 1.31/min per m2). Both the direct effect of PEEP on the CI (LOLP + HOLP vs LOHP + HOHP, p < 0.01) and the indirect effect related to the improvement in oxygenation (LOLP + LOHP vs HOLP + HOHP, p < 0.01) contributed to the reduction in CI. CONCLUSIONS: In evaluating CI changes induced by PEEP we should take into account the indirect effect of arterial oxygenation upon CI. This should be considered, at least in part, as a physiological adjustment rather than as impaired cardiovascular performance.

Adult↗
PubMed1996

7S globulin from soybean is metabolized in human cell cultures by a specific uptake and degradation system.

We examined the biological fate of 7S globulin from soybean in a hepatoma cell line (Hep G2) and in human skin fibroblasts (HSF) to gain new insights into the 7S globulin cell process, the final effect of which is an enhanced expression of the LDL-receptor. The ability of 7S globulin to bind and to be internalized and degraded by both cell types was investigated under different experimental conditions. In all cases, specific uptake (binding + internalization) and degradation of 125I-7S globulin were curvilinear functions of substrate concentration at 37 degrees C. The two processes were saturated at around 80 mg/L, a concentration at which an up-regulation of LDL-receptor was previously reported. The specific uptake of 125I-7S globulin at 37 degrees C was a curvilinear function of time, and achieved equilibrium after 6 and 12 h in HSF and Hep G2 cells, respectively. Binding experiments, conducted at 4 degrees C in Hep G2 cells, showed a specific and saturable association of 7S globulin to the cell membrane. Linear Scatchard analysis demonstrated a single population of binding sites. The amount of 7S globulin bound at saturation (Bmax) was about 2.73 mg/L, with an apparent Kd of 21 micromol/L, assuming 175 kDa as the 7S globulin molecular weight. SDS-PAGE of Hep G2 membrane proteins incubated with 125I-7S globulin revealed a specific interaction of 7S globulin with a cell protein component with molecular weight between 14 and 21 kDa. Further studies are needed to ascertain whether this interaction is directly or indirectly related to the observed stimulation of the LDL-receptor.

Carcinoma, Hepatocellular↗
PubMed1996

Effect of the new calcium antagonist lercanidipine and its enantiomers on the migration and proliferation of arterial myocytes.

The in vitro effects were investigated of the new dihydropyridine calcium antagonist (CA) lercanidipine and its enantiomers on arterial myocyte (smooth muscle cell; SMC) migration and proliferation as related to L-type calcium channel inhibition. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentration ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine, evaluated as cell number, was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. The cell doubling time increased with drug concentration < or = 122 versus 38 h for controls. The cell growth inhibition induced by lercanidipine and its enantiomers was reversible. Lercanidipine dose dependently decreased [3H]thymidine incorporation into DNA; the (R)-enantiomer, displaying the lowest CA activity, was the most potent in this respect. The tested compounds were able to inhibit fibrinogen-induced myocyte migration in a dose-dependent manner, with the (R)-enantiomer showing the more pronounced effect. To directly rule out the role of calcium channels in the antiatherosclerotic properties of lercanidipine, we examined the effect of the compounds on serum-stimulated calcium influx in SMC. Fluorimetry of Fluo 3 was used to measure changes in free cytosolic Ca2+ concentration ([Ca2+]i) in SMC after long-term preincubation (24 h) with the tested CA. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC with the (S)-enantiomer (69% inhibition) 2.4-fold more active than the counterpart and the racemate (29% inhibition). In conclusion, our in vitro results suggest that lercanidipine may directly interfere with events involved in atherogenesis. The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm at least in vitro a pharmacologic potential of the compound to negatively influence the process of atherogenesis.

Animals↗
PubMed1996

Effect of lacidipine on fatty and proliferative lesions induced in hypercholesterolaemic rabbits.

1. The in vivo antiatherogenic activity of the calcium antagonist, lacidipine, was investigated in two different types of atherosclerotic lesions (proliferative and fatty lesions) induced in rabbits. 2. The proliferative lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty lesions were induced by cholesterol feeding. Cholesterol (1%) and lacidipine (1, 3, and 10 mg kg-1) were given daily mixed with standard diet for 8 weeks to White New Zealand rabbits. The intimal hyperplasia (proliferative lesion) was induced 6 weeks after dietary and drug treatment started. 3. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals (n = 5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries with no collar (sham) showed an I/M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.62 +/- 0.12. In lacidipine-treated animals a significant and dose-dependent effect on proliferative lesions at all three doses tested, was observed. I/M ratios were 0.47 +/- 0.02, 0.40 +/- 0.09, 0.32 +/- 0.02 for doses 1, 3, and 10 mg kg-1 day-1, respectively (P < 0.05). 4. The fatty lesion extent was significantly reduced by lacidipine at the 10 mg kg-1 day-1 dose, although a trend was also observed with lower dosage. 5. These results suggest a direct antiatherosclerotic effect of lacidipine, independent of modulation of risk factors such as hypercholesterolaemia and/or hypertension. Furthermore, the proliferative lesions are apparently more sensitive to lacidipine than are lipid-rich lesions.

Animals↗
PubMed1996

Small pore size microporous membrane oxygenator reduces plasma leakage during prolonged extracorporeal circulation: a case report.

Plasma leakage has been regarded as the main technical problem during prolonged extracorporeal circulation (ECC) with microporous membrane oxygenators (MMOs). We report the case of a 15 year old male who underwent long term ECC for ARDS and in whom, by using new MMOs with reduced pore size, we were able to achieve prolonged artificial gas exchange efficiency with minimal plasma leakage. We conclude that reduced pore size MMOs might represent a valuable technical advance in extracorporeal oxygenation therapy.

Adolescent↗
PubMed1995

A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group.

BACKGROUND: Hemodynamic therapy to raise the cardiac index and oxygen delivery to supranormal may improve outcomes in critically ill patients. We studied whether increasing the cardiac index to a supranormal level (cardiac-index group) or increasing mixed venous oxygen saturation to a normal level (oxygen-saturation group) would decrease morbidity and mortality among critically ill patients, as compared with a control group in which the target was a normal cardiac index. METHODS: A total of 10,726 patients in 56 intensive care units were screened, among whom 762 patients belonging to predefined diagnostic categories with acute physiology scores of 11 or higher were randomly assigned to the three groups (252 to the control group, 253 to the cardiac-index group, and 257 to the oxygen-saturation group). RESULTS: The hemodynamic targets were reached by 94.3 percent of the control group, 44.9 percent of the cardiac-index group, and 66.7 percent of the oxygen-saturation group (P < 0.001). Mortality was 48.4, 48.6, and 52.1 percent, respectively (P = 0.638), up to the time of discharge from the intensive care unit and 62.3, 61.7, and 63.8 percent (P = 0.875) at six months. Among patients who survived, the number of dysfunctional organs and the length of the stay in the intensive care unit were similar in the three groups. No differences in mortality among the three groups were found for any diagnostic category. A subgroup analysis of the patients in whom hemodynamic targets were reached revealed similar mortality rates: 44.8, 40.4, and 39.0 percent, respectively (P = 0.478). CONCLUSIONS: Hemodynamic therapy aimed at achieving supranormal values for the cardiac index or normal values for mixed venous oxygen saturation does not reduce morbidity or mortality among critically ill patients.

Adult↗
PubMed1995

Mevalonate pathway and isoprenoids regulate human bronchial myocyte proliferation.

The role of mevalonate and geranylgeraniol in the control of cellular proliferation of cultured human bronchial myocytes was examined by investigating the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in mevalonate synthesis. Simvastatin inhibited the rate of growth of human bronchial smooth muscle cells in a concentration-dependent manner, with an IC50 value of 0.97 +/- 0.1 microM. Mevalonate (100 microM), as well as geranylgeraniol (5 microM), at their highest non-toxic concentrations, restored cell proliferation to control levels.

Bronchi↗
PubMed1995

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 farnesol or geranylgeraniol. This confirms the specific role of isoprenoid metabolites--most probably geranylgerylated 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N-nitrosourea] by simvastatin.

The effects of a combination of simvastatin, a cholesterol-lowering agent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on experimental C6 glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 microM) markedly and synergistically increased the BCNU toxicity to C6 glioma cells. The cytofluorimetric analysis of DNA from simvastatin-treated C6 glioma cells showed, besides the already described arrest in G1, an arrest/retardation in G2-M. Mitotic index from C6 cells incubated with simvastatin (10 microM) decreased by about 90%, indicating a specific C6 arrest/retardation in G2. The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultured cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G2-M compartment of the cell cycle. In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of the lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) resulted in a significant growth delay (compared to either drug alone) in C6 glioma (P < 0.05). There was no significant increase in toxicity as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in vivo support for the combined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment.

Animals↗
PubMed1995

Effects of 26-aminocholesterol, 27-hydroxycholesterol, and 25-hydroxycholesterol on proliferation and cholesterol homeostasis in arterial myocytes.

The major relation existing between cell growth and cholesterol homeostasis prompted us to investigate the effect of 26-aminocholesterol (26-NH2), 27-hydroxycholesterol (27-OH), and 25-hydroxycholesterol (25-OH) on these cellular events. To test this relation, we incubated human and rat arterial myocytes with the sterols for 72 hours. All the tested compounds (0.5 to 7.5 mumol/L) inhibited rat and human myocyte proliferation and cholesterol biosynthesis in a dose-dependent manner. 26-NH2 was more potent than oxysterols in inhibiting human myocyte proliferation but equieffective in rat cells; 27-OH and 25-OH displayed similar activity in both cell lines. Inhibition of nuclear incorporation of thymidine in rat myocytes is consistent with decreased cell count. The antiproliferative effect of the tested sterols was reversible. The high inhibition (80%) of cholesterol biosynthesis necessary to induce a decrease in myocyte proliferation suggests a causal relation between the cholesterol synthetic pathway and these cellular processes. In addition, all the tested sterols were able to inhibit hydroxymethyl glutaryl-coenzyme A reductase activity in intact myocytes but not in cell-free extracts. The finding that 26-NH2 but not 27-OH or 25-OH does not suppress LDL receptor activity in either human or rat myocytes supports the achievement of selectivity over the coordinately regulated LDL receptor gene. The ability of 26-NH2 to interfere with myocyte proliferation and cholesterol synthesis without affecting the LDL receptor pathway confers at least in vitro a pharmacological interest on the compound in the process of atherogenesis.

Animals↗
PubMed1995

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.

Animals↗
PubMed1995

Recombinant apolipoprotein A-IMilano dimer inhibits carotid intimal thickening induced by perivascular manipulation in rabbits.

Apolipoprotein A-IMilano (apoA-IM), a natural variant of apolipoprotein A-I (apoA-I), confers to the carriers a significant protection against vascular disease. The antiatherogenic activity of a recombinant disulfide-linked apoA-IM dimer (rA-IM/A-IM) was analyzed in vivo by evaluating its effect on neointimal formation induced by periarterial manipulation in 1% cholesterol-fed rabbits. A flexible collar was applied around the carotid artery 21 days after the beginning of the dietary regimen, and animals were killed 10 days later. Rabbits were injected five times with reconstituted high-density lipoprotein containing egg phosphatidylcholine (EPC) and rA-IM/A-IM (119 mg EPC + 40 mg protein per dose) or with EPC liposomes (119 mg EPC per dose) beginning either 5 days before or at the day of collar positioning. Neither treatment affected plasma cholesterol levels. A significant intimal thickening was observed in control animals; the intima-to-media (I/M) ratio was 0.63 +/- 0.11 versus 0.03 +/- 0.05 for the sham-operated contralateral arteries. Neointimal formation was markedly inhibited in animals pretreated with rA-IM/A-IM before lesion induction (I/M, 0.26 +/- 0.19) but not in those in which treatment began the day of collar insertion (I/M, 0.74 +/- 0.14). EPC liposomes did not affect neointimal formation (I/M, 0.50 +/- 0.14 and 0.51 +/- 0.07 in the two treatment groups). Proliferation of smooth muscle cells, assessed by direct incorporation of bromo-2'-deoxyuridine (BrdU) into replicating DNA, was reduced by approximately 30% and 75% in the intimal and medial tissues of rA-IM/A-IM-pretreated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

[The pharmacology of the statins: the evidence of a direct antiatherosclerotic action].

With the increasing knowledge on the pathogenesis of atherosclerosis, it appears that the prevention of cardiovascular disease in the future will involve, besides risk factor correction, direct pharmacological control of processes occurring in the arterial wall. Among them, a pivotal role is played by smooth muscle cell migration and proliferation that, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates (isoprenoids) of cholesterol synthesis are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently we provided evidence that fluvastatin, simvastatin, lovastatin, but not pravastatin, dose-dependently decrease smooth muscle cell migration and proliferation, independently of their hypocholesterolemic 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 (80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through prenylated proteins--in regulating these cellular events. The present results provide evidence that HMG-CoA reductase inhibitors interfere directly with processes involved in atherogenesis--beyond their effects on plasma lipids--partially through local inhibition of isoprenoid biosynthesis.

Animals↗
PubMed1995

Inhibition of isoprenoid biosynthesis and arterial smooth-muscle cell proliferation.

Recently, we provided in vitro and in vivo evidence that several vastatins with different potencies decrease arterial smooth-muscle cell (SMC) proliferation independently of their hypocholesterolemic properties. In this study, the in vivo dose-dependent antiproliferative activity of fluvastatin on neointimal formation induced by the insertion of a collar around one carotid artery was investigated in normocholesterolemic rabbits (five animals per treatment group). Intraperitoneal fluvastatin treatment progressively inhibited intimal to medial tissue ratios (I/M) by 5, 48, and 64% versus controls at doses of 3, 5, or 10 mg/kg/day, respectively. Local arterial delivery by an Alzet pump of mevalonate (8 mg/kg/day) at the site of collar placement fully prevented a fluvastatin (5 mg/kg/day) inhibitory effect on both I/M and SMC proliferation, as assessed by direct incorporation of bromodeoxyuridine (BrdU) into replicating DNA. The results suggest that vastatins exert a direct antiproliferative effect on intimal myocytes beyond their effects on plasma lipids, probably through local inhibition of isoprenoid biosynthesis.

Animals↗