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A Corsini

Publications and source records attributed to A Corsini.

At least 37 records · Page 2Linked to original sources
PubMed1998

Portal but not peripheral serum levels of interleukin 6 could interfere with glucose metabolism in patients with pancreatic cancer.

UNLABELLED: Interleukin 6 (IL-6), an autocrine growth factor for many tumors, seems to favour tumor spread to the liver. Our aims were first to evaluate the pattern of portal and systemic IL-6 levels in patients with pancreatic cancer (PC, n = 18) and chronic pancreatitis (CP, n = 22) compared with controls (CS, n = 20); and second, to ascertain whether there was any relation between IL-6 levels and tumor spread or PC-associated Diabetes mellitus. For all subjects, a fasting serum sample was obtained from a cubital vein; a portal serum sample was obtained from nine PC and three CP patients. In cubital and portal sera we measured IL-6, interleukin 1 beta (IL-1b), CA 19-9, c-reactive protein (CRP) and amylase. Systemic IL-6 levels were significantly higher in PC patients than in CS. In PC, portal IL-6 levels were significantly higher than the corresponding systemic values. The same pattern was found in the three CP patients, whereas IL-1b, CA 19-9, CRP and amylase portal levels were the same as systemic values. No correlation was found between PC stage and systemic or portal IL-6 levels. Portal IL-6 levels were correlated with the corresponding fasting serum glucose values. A significant correlation was found between IL-6 values and CRP, ALT, total bilirubin, GGT and creatinine, but not amylase. IN CONCLUSION: (1) Portal IL-6, which is partly of pancreatic origin, is first metabolised in the liver; (2) Systemic IL-6 reflects hepatic and renal functions rather than local conditions in the pancreas; (3) IL-6 does not appear to influence PC spread; (4) IL-6, which is released in large amounts by the inflamed pancreas, may contribute to determining diabetes, thus interfering with the signal transducing pathways involved in glucose metabolism in liver cells.

Aged↗
PubMed1998

Direct vascular effects of HMG-CoA reductase inhibitors.

Several studies have demonstrated that any beneficial effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of the enzyme reaction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, hence effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently, we provided in vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification and endocytosis of modified lipoproteins. This in vitro inhibition was completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through a prenylated protein(s)--in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluvastatin-treated patients interfere with smooth muscle cell proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids, that could translate into a more significant prevention of cardiovascular disease.

Animals↗
PubMed1998

The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved?

Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine 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. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). 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, the pharmacological potential of the compound to influence negatively the process of atherogenesis.

Animals↗
PubMed1998

Direct effects of statins on the vascular wall.

The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolemic properties. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions; thus effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently we provided in vitro and in vivo evidence of decreased smooth-muscle cell (SMC) proliferation and migration by fluvastatin and simvastatin, but not by pravastatin, independent of plasma cholesterol reduction. The ability of fluvastatin to interfere with arterial SMC proliferation at therapeutic concentrations (0.1-1 microM) prompted us to investigate the pharmacologic activity of sera from 10 patients treated with fluvastatin, 40 mg once daily, on the proliferation of cultured human arterial myocytes. Pravastatin, 40 mg once daily, displays a lipid-lowering activity similar to that of fluvastatin without affecting SMC proliferation and was investigated as a control for assessing this non-lipid-related effect of fluvastatin. Fluvastatin and pravastatin, given for 6 days to patients with type IIa hypercholesterolemia, resulted in a similar decrease in low-density-lipoprotein (LDL) cholesterol. However, the addition of 15% whole-blood sera from patients treated with fluvastatin to the culture medium resulted in a 43% inhibition of cholesterol synthesis in SMCs (p < 0.01) that mirrored the pharmacokinetic profile of fluvastatin. When SMC proliferation was investigated, a significant inhibition of cell growth (-30%; p < 0.01) was detected with sera obtained 6 h after the last dose. No effect on SMC proliferation or cholesterol biosynthesis was observed when sera from patients treated with pravastatin were evaluated. These results suggest that statins exert a direct antiproliferative effect on the arterial wall, beyond their effects on plasma lipids, which could prevent significant cardiovascular disease.

Adult↗
PubMed1998

Analysis of Helicobacter pylori vacA and cagA genotypes and serum antibody profile in benign and malignant gastroduodenal diseases.

BACKGROUND: Helicobacter pylori species comprise different strains, cytotoxic and non-cytotoxic, which can be identified on the basis of their genomic pattern. AIMS: (1) To evaluate the polymorphism of the vacA gene and to ascertain whether the cagA gene is present in patients with gastric adenocarcinoma. (2) To study the anti-H pylori antibody profile using western blotting. PATIENTS: Twenty one patients with gastric adenocarcinoma and 71 with H pylori associated benign disease (nine gastric ulcer, 29 duodenal ulcer, 25 antral gastritis, and eight duodenitis). METHODS: The polymerase chain reaction was used to verify the presence or absence of cagA and to study the polymorphism of vacA in gastric mucosal samples obtained during endoscopy for patients with benign diseases and at surgery for patients with gastric adenocarcinoma. Fasting sera were used to assess anti-H pylori antibodies against different H pylori antigens by western blotting. RESULTS: CagA gene and the allele s1 of vacA were significantly less frequent in patients with antral gastritis (60% and 60%) compared with patients with gastric adenocarcinoma (94% and 100%) and with other non-malignant gastroduodenal diseases (93% and 87%) (chi 2 = 16.01, p < 0.001; and chi 2 = 13.97, p < 0.01). In patients with gastric adenocarcinoma, antibodies against a 74 kDa H pylori antigen were less frequently found than in patients with benign diseases. CONCLUSIONS: H pylori infection caused by cagA positive/vacA s1 strains is a frequent finding in patients with gastric adenocarcinoma. Prospective studies are needed to confirm whether the low incidence of positive serological response to the 74 kDa H pylori antigen in patients with gastric adenocarcinoma is important.

Adenocarcinoma↗
PubMed1997

N-terminal peptide of type III procollagen: a possible predictor of colorectal carcinoma recurrence.

BACKGROUND: The first step of colorectal carcinoma spread depends on the ability of the tumor cells to degrade and invade the extracellular matrix (ECM). The objectives of the current study were to evaluate the serum pattern of laminin, C-terminal peptide of Type I (PIP), and N-terminal peptide of Type III (PIIIP) procollagens, markers of ECM synthesis, in the follow-up of patients after resection for colorectal carcinoma and to evaluate their role in predicting local recurrence or metastases. METHODS: A total of 32 patients who had undergone resection for colorectal carcinoma were followed for a median period of 24 months (range, 6-36 months). Every 3 months, laminin, PIP, and PIIIP were measured in the sera together with the tumor markers carcinoembryonic antigen (CEA), CA 19-9, and tissue plasminogen activator (TPA). Twenty-one patients (Group 1) had no signs of recurrence, whereas the remaining 11 (Group 2) developed hepatic (n = 7) or pulmonary (n = 4) metastases. RESULTS: No variations were observed in either group for laminin, CEA, CA 19-9, or TPA, whereas significant increases in PIP and PIIIP were observed in both groups 3 months after surgery. The increase in PIP and PIIIP at the 3-month follow-up was significantly greater in Group 1 than in Group 2. The difference between values at 3 months and basal values enabled a discrimination between Group 1 and Group 2, with a sensitivity of 36% and 91% and a specificity of 71% and 71% for PIP and PIIIP, respectively. CONCLUSIONS: The authors believe PIIIP is useful as an early prognostic indicator of recurrence in the follow-up of patients who have undergone radical resection for colorectal carcinoma.

Adult↗
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

Serum tumor markers in colorectal cancer staging, grading, and follow-up.

Early diagnosis of colorectal cancer, a frequent neoplasia in industrialized countries, permits curative surgery. In this study we assessed the clinical role of serum tumor markers determination in diagnosing, staging, and grading colorectal cancer; the role of carcinoembryonic antigen (CEA), CA 19-9, tissue polypeptide antigen (TPA) and CA 72-4 in colorectal cancer follow-up was also assessed. In 114 patients with colorectal cancer, the oncofetal antigen CEA was compared with the membrane-associated glycoproteins CA 19-9, CA 242, and CA 72-4 and with the cytokeratins TPA, tissue polypeptide-specific antigen (TPS) and tissue polypeptide monoclonal antigen (TPM). Overall, the most sensitive indices were TPA and TPS (67% and 70%, respectively). Tumor stage influenced the levels of CEA, CA 19-9, and TPA, but not those of TPS, while tumor grade influenced CEA and TPS, but not CA 72-4, TPA, and TPM. TPA was the most sensitive index in identifying early or well-differentiated colorectal cancers. The sensitivity was enhanced when this marker was determined in combination with CEA, in diagnosing both advanced and early colorectal tumors. Seventy-seven patients were followed up after therapy for at least 18 months. CEA was the most sensitive index of recurrence (58%); however, this sensitivity is too low to consider tumor markers useful in colorectal cancer follow-up.

Adult↗
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

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

Homozygous familial hypobetalipoproteinemia. Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, apo B-87Padova.

Mutations on the apolipoprotein (apo) B gene that interfere with the full-length translation of the apoB molecule are associated with familial hypobetalipoproteinemia (FHBL), a disease characterized by the reduction of plasma apoB and LDL cholesterol. In this report, we describe an FHBL kindred carrying a unique truncated apoB form, apoB-87Padova. Sequence analysis of amplified genomic DNA identified a single G deletion at nucleotide 12032, which shifts the translation reading frame and causes a termination at amino acid 3978. Two homozygous subjects and seven heterozygous relatives were studied. Although homozygous individuals had only trace amounts of LDL, they were virtually free from the symptoms typical of homozygous FHBL subjects. We investigated the in vivo turnover of radiolabeled normal apoB-100 LDL and apoB-87 LDL in one homozygous patient and two normal control subjects. ApoB-87 LDL showed a similar metabolism in all three subjects, with a fractional catabolic rate more than double that of normal LDL. The rate of entry of apoB-87 in the LDL compartment was also markedly decreased compared with normal apoB-100. The increased in vivo catabolism of apoB-87 LDL was paralleled in vitro by a 2.5-fold increased ability of these particles to inhibit the uptake and degradation of normal apoB-100 LDL by normal human cultured fibroblasts. These results indicate that apoB-87 LDL has an enhanced ability to interact with the LDL receptor, the increased apoB catabolism contributes to the hypobetalipoproteinemia and may explain the mild expression of the disease in the two homozygous individuals.

Adult↗
PubMed1996

Changing approach to gastroenteropancreatic tumours. Case report of a gastrinoma metastasis localized by somatostatin-receptor scintigraphy.

A 60-year-old female with a history of chronic pancreatitis and previous pancreaticojejunostomy has been submitted to distal gastric resection for recurrent perforating ulcers. A carcinoid tumour was identified in the surgical specimen. Hypergastrinaemia was subsequently diagnosed and tumour localization was carried out by a new scintigraphic technique with 111In-Pentetreotide. The tumour was found to be a metastasis confined to a peripancreatic lymph node. Surgery was successful, and 6 months later the patient is still eugastrinaemic. The different imaging methods for the identification of gastrinomas are discussed together with the current therapeutic options.

Duodenal Neoplasms↗
PubMed1996

Calcium, calcium antagonists and experimental atherosclerosis.

Several calcium entry blockers have shown an antiatherosclerotic effect both in vitro and in vivo. The effects are particularly evident against smooth muscle cell migration multiplication, matrix formation, calcium and cholesterol accumulation. Among the new calcium antagonists, isradipine, amlodipine and lacidipine, are promising as antiatherosclerotic agents. Lacidipine is particularly interesting because of its lipophylic structure and accumulation in cell membranes. Lacidipine is structurally related to nifedipine; we observed that lacidipine inhibits three major processes of atherogenesis: cholesteryl ester metabolism in macrophages, proliferation of myocytes, and their migration.

Animals↗
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↗