Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

Hanke, Hartmut; Oberhoff, Martin; Hanke, Sybille; Hassenstein, S.; Kamenz, Joachim; Schmid, Karl M.; Betz, E.; Karsch, Karl R.

doi:10.1161/01.cir.85.4.1548

Cited by 74 publications

(31 citation statements)

References 54 publications

(14 reference statements)

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“…As shown by a study that LMWH inhibits vessel formation in placental explants 21 , the negative effect of LMWHs on angiogenesis helps in chemotheraphy by avascularization of tumoral lesion 3 . Evaluating the effects of LMWHs on cellular proliferation after experimental balloon angioplasty in rabbits, Henke et al 22 expressed that proliferative response after angioplasty could be reduced in vivo by early treatment with LMWHs. This effect is used in humans for the same purpose and for the prevention of restenosis after by-pass graft operations 3 .…”

Section: Discussionmentioning

confidence: 99%

The effect of prophylactic dose of a low molecular weight heparin on skin wound healing of rats

et al. 2009

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Purpose:To investigate the effect of prophylactic dose of a low molecular weight heparin, enoxaparin, on skin wound healing of rats. Methods: Forty rats were used for the study. Rats were randomly assigned to two equal groups. Experimental group received prophylactic dose of enoxaparin. Physiologic saline was administered to the control group. Parameters of wound healing of experimental and control groups were compared. For comparison of the groups in terms of fibrosis, vascularization, inflammation, epithelization, and tensile strength test (Newton). Mann-Whitney-U test was used because variables were categorical data (fibrosis, vascularization, inflammation and epithelization). Differences between groups were analyzed with independent samples t-test (tensile strength). Significance was set at p<0.05. Results: Skin wound of the experimental group presented tensile strength significantly decreased (p<0.001), histopathologic examination revealed a significant (p<0.001) delayed epithelization and decreased in fibrosis, vascularization, inflammation (p<0.001) in the experimental group. Conclusion: Enoxaparin delay wound healing by decreased inflammatory cells, fibroblast contents and their products (growth factors), and by promoted hemorrhage.

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Section: Discussionmentioning

confidence: 99%

The effect of prophylactic dose of a low molecular weight heparin on skin wound healing of rats

et al. 2009

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“…The data presented indicated that LMW fucoidan reduced neointimal hyperplasia by Ϸ60% and increased the luminal area by Ϸ25%, making this compound one of the most efficient ever tested in experimental restenosis by using a noncontinuous administration regimen. 16 In contrast to heparin tested in animal models of balloon angioplasty 17,18 and clinical trials, 19 HMW fucoidan was already used at high dose (25 mg/kg in mice, 20 100 mg/kg in rats, 21 and 10 mg/kg per hour in rabbits 22 ) without bleeding. In the present study, the fraction of LMW fucoidan (8 kDa), used in rabbits at low dose (5 mg/kg), exhibited no anticoagulant activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Deux

Meddahi‐Pellé

Blanche

et al. 2002

ATVB

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Objective-Smooth muscle cell (SMC) proliferation within the intima is regulated by heparan sulfates. We studied a low molecular weight (LMW) fucoidan (sulfated polysaccharide from brown seaweed) on SMC proliferation in vitro and intimal hyperplasia in vivo. Methods and Results-In vitro study revealed that LMW fucoidan reduces rabbit SMC proliferation and is internalized in SMC perinuclear vesicles. On rabbit iliac arteries perfused in vivo with fluorolabeled LMW fucoidan after angioplasty, the labeling was mainly located on sites of injury. Pharmacokinetic studies showed that LMW fucoidan exhibited in rats an elimination half-life of 56Ϯ25 minutes (nϭ8) after intravenous administration and a constant plasma rate for Ն6 hours after intramuscular administration. After stent implantation in their iliac arteries, rabbits were also treated with LMW fucoidan (5 mg/kg IM twice a day Key Words: fucoidan Ⅲ hyperplasia Ⅲ restenosis Ⅲ stent Ⅲ vascular smooth muscle cell proliferation I ntimal hyperplasia due to migration and proliferation of smooth muscle cells (SMCs) from the media to the intima is a major component of restenosis after stent implantation. 1,2 Polysaccharides constitute a large family of molecules capable of developing molecular interactions with cellular targets within the arterial wall. 3 For instance, heparin, a natural sulfated polysaccharide, displays pleiotropic effects independent of the anticoagulant activity, including SMC growth inhibition, 4 anti-inflammatory activity, 5 and growth factor protection. 6 Fucoidan is a sulfated polysaccharide extracted from brown seaweed that reduces rat SMC proliferation in vitro in a more intensive manner than heparin. 7 We recently succeeded in producing and characterizing new homogeneous fractions of low molecular weight (LMW) fucoidan with low anticoagulant activity.The aims of the present study were to investigate the ability of LMW fucoidan to regulate vascular SMCs. For this purpose, we first tested the ability of LMW fucoidan to inhibit rabbit SMC proliferation in vitro. We explored the pharmacokinetics of LMW fucoidan injected in rats and the effect of LMW fucoidan on intimal hyperplasia. The results described below indicate that LMW fucoidan is a strong inhibitor of intimal hyperplasia and may be potentially relevant for the treatment of in-stent restenosis. Methods PolysaccharidesLMW fucoidan was isolated and hydrolyzed by a radical depolymerization process 8 from high molecular weight (HMW) extracts of brown marine algae. The characteristics of LMW fucoidan according to previously reported analytical methods 9 are as follows: weightaverage molecular mass 8Ϯ1 kDa; fucose content 35% (wt/wt); uronic acid content 3% (wt/wt); and sulfate content 34% (wt/wt). The anticoagulant activity in vitro of the LMW fucoidan was measured by an activated partial thromboplastin time (APTT), and the amount of LMW fucoidan required to obtain an APTT of 80 seconds (control 40 seconds) was 25 g/mL. 10 The anticoagulant activity in vivo of LMW fucoidan was measured in rabbit...

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“…Heparin and related compounds have been shown to inhibit SMC proliferation and migration (7)(8)(9)(10)(11)(12)(13), alter deposition of matrix proteins from SMC (13,14), and enhance endothelial regrowth after vascular injury (15)(16)(17)(18). The ability to modulate cellular activity appears to be unrelated to anticoagulant activity (19)(20)(21). The usefulness of heparin in human vascular disease, however, is limited by its requirement for parental administration, its potential bleeding complications, and its higher dose requirements for modulating SMC activity compared with the dose required for anticoagulation.…”

Section: Introductionmentioning

confidence: 99%

Sustained inhibition of intimal thickening. In vitro and in vivo effects of polymeric beta-cyclodextrin sulfate.

Bachinsky¹,

Barnathan²,

Liu³

et al. 1995

J. Clin. Invest.

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Intimal thickening after vascular injury may be modulated in part by heparin binding growth factors. We hypothesized that placement of a therapeutic polymer in the periadventitial space capable of tightly binding growth factors might alter the vascular response to injury. We first demonstrated that incubation of rat aortic smooth muscle cells with an insoluble, sulfated polymer of fi-cyclodextrin (P-CDS) was associated with a dose-dependent inhibition of proliferation induced by fetal calf serum, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor BB, or epidermal growth factor. Preincubation studies of P-CDS with FGF-2 revealed a very rapid removal of mitogenic activity. Using radiolabeled FGF-2 (0.25 ,ug/ml), we observed a very rapid association rate (0.34±0.07 min-', n = 4) and a very slow dissociation rate (3.3±0.2 x 1iO min'-) at 370C, suggesting a high affinity interaction. Using both Transwell and linear under-agarose assays, we demonstrated a significant inhibition of random migration (chemokinesis) by P-CDS. Unsulfated polymeric B-cyclodextrin (P-CD) had little if any of these effects, suggesting that the high negative charge density of P-CDS was important for the effects. Finally, rats undergoing carotid artery balloon injury were randomized to treatment with periadventitial P-CDS or no treatment, and were killed at 4 (n = 20), 14 (n = 59), and 88 d (n = 14). Morphometric analysis demonstrated significant and sustained inhibition of intimal thickening in P-CDS-treated rats at 14 (P < 0.01) and 88 d (P < 0.05) using absolute intimal area or intima/media area ratios. No inhibition was seen in a group of rats treated with P-CD. In P-CDS-treated rats, bromodeoxyuridine labeling studies revealed fewer labeled smooth muscle cells in the intima at 14 d (P = 0.01), while staining with Evans blue revealed enhanced late endothelial cell regrowth. Thus, periadventitially applied sulfated I8-cyclodextrin polymer, which can tightly bind heparin binding growth factors, inhibits intimal thickening in vivo in a sustained fashion without using an additional delivery system. These studies suggest that cellular processes mediated by heparin binding growth factors may be modulated by P-CDS. (J. Clin. Invest. 1995Invest. .96:2583Invest. -2592

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Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

Cited by 74 publications

References 54 publications

The effect of prophylactic dose of a low molecular weight heparin on skin wound healing of rats

The effect of prophylactic dose of a low molecular weight heparin on skin wound healing of rats

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Sustained inhibition of intimal thickening. In vitro and in vivo effects of polymeric beta-cyclodextrin sulfate.

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