(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Hyperplasia

Drug-eluting nanoparticles (NPs) administered by an eluting balloon represent a novel tool to prevent restenosis after angioplasty, even if the selection of the suitable drug and biodegradable material is still a matter of debate. Herein, we provide the proof of concept of the use of a novel material obtained by combining the grafting of caffeic acid or resveratrol on a poly(lactide-

Topics: Drug Carriers; Endothelial Cells; Fluvastatin; Humans; Hyperplasia; Lactic Acid; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Topics: Administration, Oral; Angioplasty, Balloon; Animals; Carotid Arteries; Carotid Artery Injuries; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Indoles; Male; Neointima; Rats, Sprague-Dawley; Rats, Zucker; Simvastatin; Species Specificity

We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured rat tail artery.. After 5 days of culture with 10% FBS, hyperplastic morphological changes in the media layer were induced. Treatment with 1 mumol/L fluvastatin significantly inhibited these changes. In the FBS-cultured arteries, the protein expression ratio of alpha-actin/beta-actin was significantly decreased, indicating the change to synthetic phenotype. Fluvastatin restored the decreased expression ratio, and the addition of mevalonate (100 mumol/L) suppressed this recovery. In accordance with the synthetic morphological changes, the absolute force of contractions induced by stimuli was decreased. Fluvastatin treatment also restored the decreased contractility, and the addition of mevalonate suppressed this recovery. In the arteries cultured with FBS, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation were significantly increased. Fluvastatin inhibited these phosphorylations, and mevalonate prevented the action of fluvastatin.. These results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation to synthetic phenotype and proliferation by inhibiting the local metabolic pathway of cholesterol in smooth muscle cells, which inhibits hyperplastic changes in the vascular wall. The antihyperplastic actions by statins may be induced by inhibiting the ERK1/2 and p38MAPK activities, possibly through inhibition of prenylated Ras. We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured artery. Results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation and proliferation by inhibiting the ERK1/2 and p38MAPK activities through depletion of mevalonate in smooth muscle cells, resulting in inhibiting vascular hyperplastic changes.

Topics: Animals; Arteries; Cell Division; Cholesterol; Culture Media, Serum-Free; Fatty Acids, Monounsaturated; Fluvastatin; Hyperplasia; Indoles; Male; Mevalonic Acid; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Organ Culture Techniques; p38 Mitogen-Activated Protein Kinases; Phenotype; Protein Kinase Inhibitors; Protein Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Rats; Rats, Wistar; Signal Transduction; Tail; Vasoconstriction

Intimal hyperplasia is a vascular remodelling process that occurs after a vascular injury. The mechanisms involved in intimal hyperplasia are proliferation, dedifferentiation, and migration of medial smooth muscle cells towards the subintimal space. We postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, might participate in the development of intimal hyperplasia. Connexin43 (Cx43) expression levels may be altered in intimal hyperplasia, and we therefore evaluated the regulated expression of Cx43 in human saphenous veins in culture in the presence or not of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity.. Segments of harvested human saphenous veins, obtained at the time of bypass graft, were opened longitudinally with the luminal surface uppermost and maintained in culture for 14 days. Vein fragments were then processed for histologic examination, neointimal thickness measurements, immunocytochemistry, RNA, and proteins analysis.. Of the four connexins (Cx37, 40, 43, and 45), we focused on Cx43 and Cx40, which we found by real-time polymerase chain reaction to be expressed in the saphenous vein because they are the predominant connexins expressed by smooth muscle cells and endothelial cells. After 14 days of culture, histomorphometric analysis showed a significant increase in the intimal thickness as observed during the process of intimal hyperplasia. A time-course analysis revealed a progressive upregulation of Cx43 to reach a maximal increase of sixfold to eightfold at both transcript and protein levels after 14 days in culture. In contrast, the expression of Cx40, abundantly expressed in the endothelial cells, was not altered. Immunofluorescence showed a large increase in Cx43 within smooth muscle cell membranes of the media layer. The development of intimal hyperplasia in vitro was decreased in presence of fluvastatin and was associated with reduced Cx43 expression.. These data show that Cx43 is increased in vitro during the process of intimal hyperplasia and that fluvastatin could prevent this induction, supporting a critical role for Cx43-mediated gap-junctional communication in the human vein during the development of intimal hyperplasia.. Stenosis due to intimal hyperplasia is the most common cause of failure of venous bypass grafts. To better understand the development of intimal hyperplasia, we used an ex vivo organ culture model to study saphenous veins harvested from patients undergoing a lower limb bypass surgery. In this model, the morphologic and functional integrity of the vessel wall is maintained and significant intimal hyperplasia development occurs after 14 days in culture. We have postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, may participate in the development of intimal hyperplasia. Indeed, intimal hyperplasia consists of proliferation and migration of smooth muscle cells into the subendothelial space. Intercellular communication is responsible for the direct transfer of ions and small molecules from one cell to the other through gap-junction channels found at cell-cell appositions. No study to date has evaluated whether gap junctional communication is involved in the process of intimal hyperplasia in humans. This assertion was investigated by using the aforementioned organ culture model of intimal hyperplasia in human saphenous veins, and our data support a critical role for Cx43-mediated gap junctional communication in human vein during the development of intimal hyperplasia.

Topics: Blotting, Western; Cell Differentiation; Cells, Cultured; Connexin 43; Endothelial Cells; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gap Junctions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Indoles; Male; Middle Aged; Organ Culture Techniques; Reverse Transcriptase Polymerase Chain Reaction; Saphenous Vein; Tunica Intima

The expression of tissue factor (TF), mainly by infiltrated inflammatory cells, has been shown to be responsible for the thrombogenicity associated with atheroma. The contribution of the nonlipid-related effects of statins to the clinical benefits of statin therapy is currently under intense investigation. In this study, we evaluated the ability of fluvastatin to modulate TF expression and macrophage accumulation in rabbit carotid intimal lesions independently of cholesterol lowering. Male rabbits were fed for 30 days a 1% cholesterol-rich diet with or without fluvastatin at 5 mg/kg per day. Two weeks from the start of treatment, a silastic collar was placed around the carotid artery. Fifteen days later, the animals were killed, and carotid segments were excised and processed. The atherogenic diet caused a consistent increase in plasma cholesterol levels (610+/-231 mg/dL versus 50+/-9 mg/dL at baseline), which were not affected by fluvastatin (603+/-248 mg/dL). In the rabbits fed a high cholesterol diet without fluvastatin, an intimal lesion with macrophage accumulation and TF expression was detected. Fluvastatin significantly reduced TF and macrophage content of the lesion (-50% for both). Results indicate that fluvastatin may attenuate the inflammatory and thrombogenic potential of atherosclerotic lesions through a mechanism(s) other than cholesterol reduction, providing new insight regarding the complex mode of action of statins.

Topics: Animals; Anticholesteremic Agents; Carotid Artery Diseases; Cholesterol; Diet, Atherogenic; Fatty Acids, Monounsaturated; Fluvastatin; Hyperplasia; Indoles; Ligation; Macrophages; Male; Rabbits; Thromboplastin; Tunica Intima

The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation.

Topics: Anticholesteremic Agents; Atorvastatin; Case-Control Studies; Coronary Angiography; Coronary Disease; Disease-Free Survival; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Heptanoic Acids; Humans; Hyperplasia; Indoles; Lovastatin; Male; Middle Aged; Pyrroles; Recurrence; Retrospective Studies; Simvastatin; Stents; Time Factors; Tunica Intima

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.

Topics: Animals; Anticholesteremic Agents; Catheterization; Cholesterol; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Femoral Artery; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Indoles; Lipids; Male; Mevalonic Acid; Phospholipids; Pravastatin; Rabbits; Triglycerides; Tunica Intima