Fluvastatin Prevents Vascular Hyperplasia by Inhibiting Phenotype Modulation and Proliferation Through Extracellular Signal-Regulated Kinase 1 and 2 and p38 Mitogen-Activated Protein Kinase Inactivation in Organ-Cultured Artery

Abstract

Objective-We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured rat tail artery. Methods and Results-After 5 days of culture with 10% FBS, hyperplastic morphological changes in the media layer were induced. Treatment with 1 mol/L fluvastatin significantly inhibited these changes. In the FBS-cultured arteries, the protein expression ratio of ␣-actin/␤-actin was significantly decreased, indicating the change to synthetic phenotype. Fluvastatin restored the decreased expression ratio, and the addition of mevalonate (100 mol/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. Key Words: fluvastatin Ⅲ mevalonate Ⅲ organ culture Ⅲ smooth muscle hypertrophy Ⅲ phenotypic modulation 3 -Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, are drugs that decrease the plasma lipid concentration by inhibiting HMG-CoA reductase, a ratelimiting enzyme for the cholesterol biosynthesis, in hepatic cells. 1 In addition, their ability to reduce cholesterol synthesis, which is linked to their local hypocholesterolemic properties, helps prevent cardiovascular events, 2 including clinical trials. 3-5 HMG-CoA reductase intracellularly metabolizes HMG-CoA to mevalonic acid, which is the precursor of numerous bioactive metabolites, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Therefore, statins can potentially have pleiotropic effects on vascular physiology by inhibiting HMG-CoA reductase apart from their blood lipid-lowering effects. 6 -12 For instance, statins can interfere with formation of atherosclerotic lesions through the mechanisms modifying endothelial function, vasomotor function, inflammatory responses, plaque stability, and vascular smooth muscle cell (VSMC) proliferation. 8,11,13,14 VSMC proliferation is a central event in the pathogenesis of vascular lesions such as atherosclerosis, postangioplasty restenosis, or transplant arteriosclerosis. 15,16 Hypercholesterolemia, modified lipids, lipoproteins, hypertension, and infection promote vascular inflammation, which induces vascular hyperplastic responses with VSMC proliferation. It has also been well established that many immune reactive cells such as T cells and macrophages and nonimmune cells such as endothelial cells produce inflammatory cytokines, chemokines, and growth factors to change phenotype modulation for synthetic state and to proliferate VSMCs. 14 In hyperplastic vascular lesions, VSMC phenotype modulates from a contractile phenotype to a synthetic phenotyp...

Simvastatin Ameliorates Rat Cerebrovascular Remodeling During Hypertension via Inhibition of Volume-Regulated Chloride Channel

“…These data demonstrated that simvastatin inhibited BASMC proliferation via modifying Rho geranylgeranylation. Although several molecules, such as p21 kip1 and extracellular regulated kinase, 32,33 have been reported to mediate the functional roles of Rho signaling in the regulation of cell proliferation, the downstream effectors of active Rho remain elusive.…”

“…These data demonstrated that simvastatin inhibited BASMC proliferation via modifying Rho geranylgeranylation. Although several molecules, such as p21 kip1 and extracellular regulated kinase, 32,33 have been reported to mediate the functional roles of Rho signaling in the regulation of cell proliferation, the downstream effectors of active Rho remain elusive.During the early phase of cell proliferation, cells undergo swelling because of water influx, which accompanies the uptake of nutrients necessary for cell metabolism. An increase in cell volume will initiate the regulatory volume decrease process through activation of ion (K and Cl) channels and transporters, which activates K and Cl efflux to normalize the cell size.…”

Time-Dependent Phenotypic and Contractile Changes of Pulmonary Artery in Chronic Hypoxia–Induced Pulmonary Hypertension

“…Immunohistochemical staining with BrdU proceeded as described by Sakamoto et al (25). In brief, rats were injected intraperitoneally with 100 mg/kg of BrdU at 48 and 24 h before sacrifice, and 6-μm-thick sections were prepared and stained using the Vector ABC kit (Vector Laboratories Inc., Burlingame, CA, USA).…”

Bayesian statistic methods and theri application in probabilistic simulation models

“…Le statine disponibili differiscono per alcune caratteristiche chimico-fisiche (solubilità), farmacocinetiche (assorbimento, legame proteico, metabolismo ed escrezione), farmacodinamiche (potenza relativa ed effetti pleiotropici) [2,[20][21].…”