Lipoprotein inhibiting factors

Tissue factor pathway inhibitor (TFPI) is a major physiologic inhibitor of coagulation. It is a protein that circulates in the blood associated with lipoproteins. TFPI directly inhibits factor Xa by binding to the enzyme near its active site. This factor Xa-TFPI complex then inhibits the factor Vlla-tissue factor complex. 

B51. Broze, G. J., Warren, L. A., Novotny, W. F., Higuchi, D. A., Girard, J. J., and Miletich, J. P The lipoprotein-associated coagulation inhibitor which inhibits the factor Vll-tissue factor complex also inhibits factor Xa Insight into its possible mechanism of action. Blood 71,335-343 (1988). 

Ohlsson, B.C., Englund, M.C., Karlsson, A.L., Knutsen, E., Erixon, C, Skribeck, H., Liu, Y., Bondjers, G., and Wiklund, O., 1996, Oxidized low density lipoprotein inhibits hpopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1 beta in macrophages, J. Clin. Invest. 98 78-89. 

Fig. 1. Oxidation hypothesis. Proposes minimally modified LDL is formed due to oxidation in the arterial intimal space. This LDL can still be taken up by the LDL receptor, but minimally modified LDL promotes release of proinflammatory mediators from monocytes and acts as a monocyte inhibition factor (MIF), reducing the motility of monocytes and thus leading to recruitment of macrophages (J4, W9). Macrophages further oxidize LDL (OxLDL), release inflammatory mediators, and rapidly take up OxLDL and other lipoproteins via the unregulated scavenger receptor that binds modified apo B to form lipid-laden foam cells. OxLDL is cytotoxic to a variety of cells in culture and may disrupt endothelial tissue, causing the release of inflammatory mediators and the entry of more LDL into the intimal space. Continued accumulation of monocytes and their differentiation into macrophages leads to a vicious cycle (J4, W9). Adapted from reference J4.

Probucol, another di-r-butyl phenol, is an anti-atherosclerotic agent that can suppress the oxidation of low-density lipoprotein (LDL) in addition to lowering cholesterol levels. The antioxidant activity of probucol was measured, using EPR, with oxidation of methyl linoleate that was encapsulated in liposomal membranes or dissolved in hexane. Probucol suppressed ffee-radical-mediated oxidation. Its antioxidant activity was 17-fold less than that of tocopherol. This difference was less in liposomes than in hexane solution. Probucol suppressed the oxidation of LDL as efficiently as tocopherol. This work implies that physical factors as well as chemical reactivity are important in determining overall lipid peroxidation inhibition activity (Gotoh et al., 1992). 

The antithrombotic factors produced by endothelial cells are thrombomodulin (TM) and protein S (PS), components of the vitamin K-dependent protein C (PC) anticoagulant pathway, inhibiting F-Va-F-Villa (E15) tissue plasminogen activator (tPA), responsible for fibrinolysis (N2, LI8) and the lipoprotein-associated coagulation inhibitor (LACI), which inhibits F-VIIa-TF complex and F-Xa (B51). 

The physiological function of heparin is not completely understood. It is found only in trace amounts in normal circulating blood. It exerts an antihpemic effect by releasing lipoprotein lipase from endothehal cells heparinlike proteoglycans produced by endothelial cells have anticoagulant activity. Heparin decreases platelet and inflammatory cell adhesiveness to endothelial cells, reduces the release of platelet-derived growth factor, inhibits tumor cell metastasis, and exerts an antiproliferative effect on several types of smooth muscle. 

NO also reduces endothelial adhesion of monocytes and leukocytes, key features of the early development of atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial surface. In addition, NO may act as an antioxidant, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also affected by NO-dependent reduction in endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals deficient in eNOS by pharmacologic inhibition. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus enhance atherogenesis. 

High-density lipoproteins (HDL) exert several ant/atherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus are a target for intervention. 

Leitinger N., Watson A. D., Faull K. F., Fogelman A. M., and Berliner J. A. (1997). Monocyte binding to endothelial cells induced by oxidized phospholipids present in minimally oxidized low density lipoprotein is inhibited by a platelet activating factor receptor antagonist. Adv. Exp. Med. Biol. 433 379-382. 

Normal serum was recently demonstrated to contain substances inhibiting permeability factor(s). These inhibitors are not present in sera of patients with FSGS (Sll). Some of these inhibitors have been identified as apolipoproteins of the high-density lipoprotein (HDL) complex, for example, apo J, apo E2, and apo E4 (C2). Inhibitors of the permeability factors may be lost in urine in patients with nephrotic syndrome and their presence in urine has been documented (G5). FSGS may thus be caused not only by the (increased) production of permeability factors, but also by the urinary loss of their inhibitors. Bioassay (S5) is not able to differentiate between increased production of permeability factors and the loss of their inhibitors. Increased permeability was confirmed by this bioassay even in patients with FSGS and the documented mutation of the podocin gene, apparently without increased production of the permeability factors (G5). 

It has been clear for several decades that an elevated concentration of plasma cholesterol attributable to increased concentrations of atherogenic lipoproteins (low-density lipoproteins [LDL] and remnant lipoproteins) is a major risk factor for the development of coronary heart disease (CHD) (Castelli et al., 1992 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 1993). The cholesterol biosynthetic pathway (Fig. 1) was a natural target in the search for drugs to reduce plasma cholesterol concentrations in the hope that these treatments would reduce the risk of CHD. However, early attempts to reduce cholesterol biosynthesis were disastrous. Tri-paranol, which inhibits the penultimate step in the pathway, was introduced into clinical use in the mid-1960s but was withdrawn from the... 

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