Wolfgang Borth

Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasia

We previously reported that heparin inhibits the proliferation of fibroblasts and vascular smooth muscle cells (SMC), in part, by binding to and increasing the antiproliferative activity of transforming growth factor-beta 1 (TGF-beta 1). We now report that certain other polyanions which are structurally distinct from heparin, such as fucoidan and polyinosinic acid, are more avid ligands for TGF-beta 1 and more potent antiproliferative agents than heparin. Fucoidan possessed more potent antiproliferative activity than heparin against rat and bovine aortic SMC in vitro, though possessing much lower anticoagulant activity than heparin. Furthermore, fucoidan suppressed in vivo intimal hyperplasia when continuously infused into rats subjected to balloon-catheter injury. Unlike heparin, which also suppressed intimal hyperplasia, fucoidan did not cause systemic anticoagulation. Thus, fucoidan may be useful as a non-anticoagulant inhibitor of post-angioplasty intimal hyperplasia.

Identification of mechanisms that may modulate the role of lipoprotein(a) in thrombosis and atherogenesis

In this report, we review recent findings concerning the identification of mechanisms that may modulate the role of lipoprotein(a), or Lp(a), in thrombosis and atherogenesis. Lp(a) binds to surface-immobilized plasmin-modified fibrin, thus providing a mechanism for incorporating Lp(a) into the vessel wall. We found that homocysteine and other sulfhydryl-containing amino acids markedly increase the binding of Lp(a) to plasmin-modified fibrin. Our results suggest that homocysteine alters the structure of Lp(a) to expose lysine-binding sites on the apolipoprotein(a) portion of the molecule, and thus provide a potential biochemical link between thrombosis and atherogenesis. We also found that transglutaminases catalyze the incorporation of primary amines into Lp(a). Studies in cell culture systems have found that Lp(a) stimulates endothelial cells to synthesize and release plasminogen activator inhibitor-1. Further, Lp(a) inhibits the activation of transforming growth factor-beta in a coculture of bovine endothelial and smooth muscle cells.

Lipoprotein(a), Homocysteine, and Atherogenesis

An elevated blood level of lipoprotein(a) is an independent risk factor for coronary and carotid artery atherosclerosis leading to premature myocardial infarction and stroke. Elevated liproprotein(a) is also associated with restenosis following coronary balloon angioplasty. The mechanisms by which lipoprotein(a) promote the atherosclerotic process are not clear. The apolipoprotein(a) portion of lipoprotein(a) shares partial homology with plasminogen, the precursor of plasmin, the fibrinolytic protease. Our studies have documented that lipoprotein(a) binds to fibrin, and that partial degradation of fibrin by plasmin increases binding. These findings parallel immunohistochemical studies showing colocalization of lipoprotein(a) with fibrin in atheromatous plaques, suggesting that the lipoprotein(a)-fibrin interaction may be atherogenic. We have found that homocysteine, at concentrations as low as 8 M, increased the binding of lipoprotein(a) to fibrin. Homocysteine induced a 20-fold increase in the affinity of lipoprotein(a) for plasmin-modified fibrin as compared to the binding in the absence of homocysteins. Our data indicate that homocysteine and other agents containing free sulfhydryl groups alter the lipoprotein(a) particle so as to increase the reactivity of the plasminogen-like apolipoprotein(a) portion. These observations suggest a biochemical link between lipoprotein(a), sulfhydryl compound metabolism, thrombosis, and atherogenesis.