Fucoidan Inhibits Smooth Muscle Cell Proliferation and Reduces Mitogen-activated Protein Kinase Activity

Religa, Piotr; Kazi, Monsur; Thyberg, Johan; Gaciong, Zbigniew; Swedenborg, Jesper; Hedin, Ulf

doi:10.1053/ejvs.2000.1220

Cited by 49 publications

(30 citation statements)

References 41 publications

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“…In agreement with previous studies using HMW fucoidan in cultured rat and human SMCs, 7,23,24 LMW fucoidan reduced rabbit SMC proliferation in vitro and appeared to be a more antiproliferative agent than LMW heparin. Our confocal microscopy studies show that LMW fucoidan has high affinity for cultured SMCs and is internalized in perinuclear endocytotic vesicles.…”

Section: Discussionsupporting

confidence: 92%

“…12,26 Perinuclear localization of LMW fucoidan suggests an antiproliferative activity via intracellular signaling pathways. 23,24 We also observed that after angioplasty and local injection of LMW fucoidan in rabbit iliac arteries, the polysaccharide was located on the injured segment of the artery, whereas a low binding was noticed on the artery without angioplasty. This preferential binding in vivo after injury by angioplasty strongly suggested a favorable location of the LMW fucoidan to inhibit SMC activation and proliferation.…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

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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“…This is in agreement with work done by Ferro et al 36) and similar to results observed using other cell systems such as smooth muscle cells. 37) Addition of TGF-b 1 to fibroblast monolayers dramatically reduced fibroblast proliferation. One of the commercial preparations of fucoidan which we used, F7, reversed the effect TGF-b 1 on cell proliferation and caused a relative increase in fibroblast cell number whereas the other one, fucoidan FF, a different preparation, did not exhibit similar properties.…”

Section: Discussionmentioning

confidence: 96%

Fucoidan Modulates the Effect of Transforming Growth Factor (TGF)-.BETA.1 on Fibroblast Proliferation and Wound Repopulation in in Vitro Models of Dermal Wound Repair

O’Leary

Rerek²,

Wood

2004

Biological & Pharmaceutical Bulletin

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“…Despite the direct in vitro and in vivo inhibitory effects of HMW and LMW fucoidan on vascular smooth muscle cell growth (McCaffrey et al, 1992;Logeart et al, 1997a,b;Deux et al, 2002), our results indicate that LMW fucoidan potentiates the effect of FGF-2 on [ 3 H]thymidine uptake. We have extended these concepts to experimental therapeutics, showing that LMW fucoidan promotes FGF-2 effects in vivo, suggesting its potential interest for use in vascular tissue repair (Deux et al, 2002) and angiogenesis (Religa et al, 2000;Matou et al, 2002).…”

Section: Therapeutic Revascularization With Low-molecular Weight Fucomentioning

confidence: 99%

Low-Molecular-Weight Fucoidan Promotes Therapeutic Revascularization in a Rat Model of Critical Hindlimb Ischemia

Luyt¹,

Meddahi‐Pellé²,

Ho‐Tin‐Noé³

et al. 2003

J Pharmacol Exp Ther

121

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The therapeutic potential of low-molecular-weight (LMW) fucoidan, a sulfated polysaccharide extracted from brown seaweed devoid of direct antithrombin effect, was investigated in vitro and in a model of critical hindlimb ischemia in rat. In vitro results showed that LMW fucoidan enhanced fibroblast growth factor (FGF)-2-induced [ 3 H]thymidine incorporation in cultured rat smooth muscle cells. Intravenous injection in rats of LMW fucoidan significantly increased the stromal-derived factor (SDF)-1 level from 1.2 Ϯ 0.1 to 6.5 Ϯ 0.35 ng/ml in plasma. The therapeutic effect of LMW fucoidan (5 mg/kg/day), FGF-2 (1 g/kg/day), and LMW fucoidan combined with FGF-2 was assessed 14 days after induction of ischemia by 1) clinical evaluation of claudication, 2) tissue blood flow analysis, 3) histoenzymology of muscle metabolic activity, and 4) quantification of capillary density. Both LMW fucoidan and FGF-2 similarly improved residual muscle blood flow (62.5 Ϯ 6.5 and 64.5 Ϯ 4.5%, respectively) compared with the control group (42 Ϯ 3.5%, p Ͻ 0.0001). The combination of FGF-2 and LMW fucoidan showed further significant improvement in tissue blood flow (90.5 Ϯ 3%, p Ͻ 0.0001). These results were confirmed by phosphorylase activity, showing muscle regeneration in rats treated with the combination of FGF-2 and LMW fucoidan. Capillary density count increased from 9.6 Ϯ 0.7 capillaries/muscle section in untreated ischemic controls to 14.3 Ϯ 0.9 with LMW fucoidan, 14.5 Ϯ 0.9 with FGF-2, and 19

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Fucoidan Inhibits Smooth Muscle Cell Proliferation and Reduces Mitogen-activated Protein Kinase Activity

Abstract: fucoidan is a more potent anti-proliferative polysulphated polysaccharide than heparin and may mediate its effects through inhibition of the mitogen-activated protein kinase pathway in a similar manner as heparin.

Cited by 49 publications

References 41 publications

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

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

Fucoidan Modulates the Effect of Transforming Growth Factor (TGF)-.BETA.1 on Fibroblast Proliferation and Wound Repopulation in in Vitro Models of Dermal Wound Repair

Low-Molecular-Weight Fucoidan Promotes Therapeutic Revascularization in a Rat Model of Critical Hindlimb Ischemia

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