The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury

Wu, Chieh Hsi; Pan, Chun Hsu; Chang, Wen Shin; Hung, Jui‐Sung; Mao, Simon J.T.

doi:10.1007/s11373-005-6900-5

Cited by 15 publications

(10 citation statements)

References 36 publications

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“…The polymer used in this study for local delivery of epothilone B was F-127 Pluronic gel as described previously (Wu et al, 2005). This polymer has a novel property of being soluble at 4°C, while solidifying on contact with tissues at 37°C.…”

Section: Discussionmentioning

confidence: 99%

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Lim

Kim²,

Jin³

et al. 2007

J Pharmacol Exp Ther

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The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. Epothilone B, a novel potential antitumor compound, has a potent effect on preventing postangioplasty restenosis. Therefore, we established an in vivo rat carotid injury model and examined the potential effects of epothilone B on cardiovascular disease. We found that epothilone B potently prevented neointimal formation and in vivo VSMCs proliferation. In addition, we also showed that epothilone B significantly inhibited 5% fetal bovine serum (FBS)-and 50 ng/ml plateletderived growth factor (PDGF)-BB-induced proliferation and cell cycle progression in rat aortic VSMCs. Furthermore, FBS and PDGF-BB induced the activations of extracellular signal-regulated kinases 1 and 2, Akt, phospholipase C ␥ 1, and PDGFreceptor ␤ chain tyrosine kinase were not changed by epothilone B. However, epothilone B treatment caused a significant decrease in the level of cyclin-dependent protein kinase (CDK) 2, whereas it caused no change in the levels of cyclin E and down-regulated the phosphorylation of retinoblastoma, which plays a critical role in cell cycle regulation. Furthermore, levels of p27, an inhibitor of cyclin E/CDK2 complex, were significantly increased in VSMCs treated with epothilone B, indicating that this might be a major molecular mechanism for the inhibitory effects of epothilone B on the proliferation and cell cycle of VSMCs. These findings suggest that epothilone B can inhibit neointimal formation via the cell cycle arrest by the regulation of the cell cycle-related proteins in VSMCs.Proliferation and migration of vascular smooth muscle cells (VSMCs) play a pivotal role in the development of restenosis and in the progression of atherosclerosis (Ross, 1993). Arterial injury results in the migration of VSMCs into the intimal layer of the arterial wall, where they proliferate and synthesize extracellular matrix components. Many growth factors induce the proliferation of VSMCs in vitro and in vivo. Among them, platelet-derived growth factor (PDGF) and basic fibroblast growth factor are important regulators of VSMC behavior through their well defined actions as potent chemoattractants and strong mitogens. Administration of these growth factors enhances intimal thickening after angioplasty in rat, whereas injection of antibodies or use of antisense technology to block signal transduction by either of these growth factors potently inhibits postinjury intimal hyperplasia in rat and restenosis in pig, suggesting that VSMC growth plays an important role in the pathogenesis of these models.Arterial injury during percutaneous transluminal coronary angioplasty induces multiple signaling pathways that activate VSMC migration and proliferation. Immediately after injury, VSMCs leave their quiescent state and enter the cell

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Section: Discussionmentioning

confidence: 99%

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Lim

Kim²,

Jin³

et al. 2007

J Pharmacol Exp Ther

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“…An inflated balloon was pushed and pulled through the lumen three times to damage the vessel. The six groups of the animals include sham (no angioplasty), balloon-injured alone, and four doses of EDS (10,20,40 and 80 mg/kg) given to rats daily for 2 weeks before and after balloon injury via gastric intubation (7,19) . At 2 weeks after balloon injury, rats were killed with an over dose of pentobarbital by injection.…”

Section: Balloon Angioplastymentioning

confidence: 99%

Molecular mechanism of green microalgae,Dunaliella salina, involved in attenuating balloon injury-induced neointimal formation

et al. 2010

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The pathological mechanism of restenosis is primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMC). The preventive effects of ethanol extract of Dunaliella salina (EDS) on balloon injury-induced neointimal formation were investigated. To explore its molecular mechanism in regulating cell proliferation, we first showed that EDS markedly reduced the human aortic smooth muscle cell proliferation via the inhibition of 5 0 -bromo-2 0 -deoxyuridine (BrdU) incorporation at 40 and 80 mg/ml. This was further supported by the G 0 /G 1 -phase arrest using a flow cytometric analysis. In an in vivo study, EDS at 40 and 80 mg/ml was previously administered to the Sprague -Dawley rats and found that the thickness of neointima, and the ratio of neointima:media were also reduced. EDS inhibited VSMC proliferation in a dose-dependent manner following stimulation of VSMC cultures with 15 % fetal bovine serum (FBS). Suppressed by EDS were 15 % FBS-stimulated intracellular Raf, phosphorylated extracellular signal-regulated kinases (p-Erk) involved in cell-cycle arrest and proliferating cell nuclear antigen. Phosphorylated focal adhesion kinase (p-FAK) was also suppressed by EDS. Also active caspase-9, caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) protein expression levels were increased by administration with EDS; the apoptotic pathway may play an important role in the regulatory effects of EDS on cell growth. These observations provide a mechanism of EDS in attenuating cell proliferation, thus as a potential intervention for restenosis.Human aortic smooth muscle cells: Angioplasty: Neointima formation: Restenosis: Dunaliella salina Dunaliella salina, Teod. (Chlorophyceae), the unicellular halophilic green microalga, is known as a major source of b-carotene. Administration of D. salina decreased the levels of cholesterol and lactate dehydrogenase as well as increasing the activities of catalase, superoxide dismutase, serum aspartate aminotransaminase and serum alanine aminotransferase (1) . Aside from being a precursor for vitamin A, D. salina has also been known to possess a potent antioxidant activity, as shown in an in vivo study (2) . Analysing the constituents of an ethanol extract of D. salina (EDS) in our previous study demonstrated 6 % of b-carotene, 0·12 % of a-carotene, 0·2 % of xanthophyll, 0·3 % of zeaxanthin, and scarse amounts of lycopene and chlorophyll (3) . It has been shown that 9-cis b-carotenerich powder of the alga D. bardawil increases plasma HDLcholesterol in fibrate-treated patients (4) . Levy et al. found a significant increase in the lag time of oxidising LDLcholesterol following a 3-week b-carotene supplementation (60 mg/d), suggesting the antioxidant effects of b-carotene (5) .Percutaneous transluminal coronary angioplasty (PTCA) has been used in patients with angina and acute myocardial infarction (6) . However, restenosis in about 30 % of patients within 6 months following the angioplasty procedure has been a major disadvantage of this therapy (7) . Stents were ...

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“…In addition, in an in vivo study, when the pluronic gel containing 80 nM and 80 lM actinomycin D was applied topically to surround the rat carotid adventitia; the thickness of neointima was substantially reduced (45 and 55%, respectively). The protein expression levels of proliferating cell nuclear antigen D (PCNA), focal adhesion kinase (FAK), and Raf were all suppressed by actinomycin D. This study provides a detailed mechanism of action by actinomycin D in preventing cell proliferation, thus as a potential intervention for restenosis [16].…”

Section: Molecular Mechanism Of Actinomycin D On Restenosismentioning

confidence: 87%

Biomedical Vignette

2005

J Biomed Sci

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The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury

Cited by 15 publications

References 36 publications

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Molecular mechanism of green microalgae,Dunaliella salina, involved in attenuating balloon injury-induced neointimal formation

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