Oxidized low-density lipoprotein associates strongly with carboxy-terminal domain of tissue factor pathway inhibitor and reduces the catalytic activity of the protein

Tissue factor pathway inhibitor (TFPI) is a physiological protease inhibitor of the extrinsic blood coagulation pathway. Previously we have shown that TFPI associates quite rapidly with oxidized low-density lipoprotein (ox-LDL), with a reduction of the inhibitory activity on factor X activation. In the present study, it was found, by means of agarose gel electrophoresis, that the pre-incubation of full-length rTFPI with heparin or the carboxy (C)-terminal part (peptide 240-265) of TFPI prevented the association with ox-LDL in a dose-dependent manner. When rTFPI lacking the C-terminal basic part of the molecule (rTFPI-C) was mixed with ox-LDL, only a small amount of rTFPI-C was shifted to the position of ox-LDL on electrophoresis. Further, ox-LDL did not reduce the activity of rTFPI-C. These results indicate that the C-terminal domain of TFPI molecule plays a predominant role in the binding to ox-LDL and the binding through the C-terminal part is essential for the ox-LDL-dependent reduction of the anticoagulant activity of TFPI.     

Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody

We investigated anti-annexin V antibody (aANX) in patients with systemic lupus erythe-matosus (SLE), and correlated to positivity with lupus anticoagulant (LA)/anticardiolipin antibody (aCL). aANX was positive in 12/47 SLE patients (26%), including 7 with β₂-glycoprotein 1 (GPl)-dependent aANX. The positivity of aANX was higher in patients with aCL (19%) and LA/aCL (50%) than in those without LA/aCL (10%). From these results, it is concluded that aANX is an autoantibody closely related to LA/aCL, and can be a possible new risk marker for thrombosis. © 1994 Wiley-Liss, Inc.     

Immuno-Morphological Study in Tuberculosis, Especially the Lesions Caused by Dead Tubercle Bacilli Embedded in Paraffin-oil

The extensively widespread occurrence of the lesions caused by dead tubercle bacilli embedded in paraffin-oil may be essential for the establishment of the state of hypersensitivity, even if such lesions may be an innocent tuberculoid change. And the fact that the lesions or metastatic foci are chiefly formed by invading the lymph channels, may probably play an important role in the mechanism of the occurrence of such innocent tuberculoid changes.
Therefore, the tuberculo-immunity premises the existence of tuberculous change; namely, it is exactly similar to that of typhoid fever.     

Measurement of β2-glycoprotein i (apolipoprotein h)-independent anticardiolipin antibody in human immunodeficiency virus-1-positive and-negative hemophiliacs

The authors studied whether or not anticardiolipin antibody (aCL), which is frequently detected in hemophiliacs with human immunodeficiency virus-1 (HIV-1) infection, is dependent on β₂-glycoprotein I (GPI), a cofactor of cardiolipin (CL). GPI-independent aCL was positive in 27 of 36 hemophiliacs with HIV-1 antibody (75%) and in 23 of 29 patients without HIV-1 antibody (79%). However, only six HIV-1-positive and four HIV-1-negative patients were positive for GPI-dependent aCL. Thus the aCL in these hemophiliacs was GPI independent and therefore different from the aCL found in autoimmune diseases, such as systemic lupus erythematosus.     

Sole existence of antithrombin antibody in patients with systemic lupus erythematosus showing tendency of its antigenic determinants directing against exosite II (antithrombin/heparin binding site) of thrombin.

We conducted an investigation to determine the antigenic determinants of antithrombin antibody (aThr), which has recently been recognized as a new antiphospholipid antibody mostly co-existing with antiprothrombin antibody, employing patients with systemic lupus erythematosus and antiphospholipid syndrome. Using an enzyme-linked immunosorbent assay we found aThr in 34 of 83 patients (40.9%), and 27 of these 34 patients (79.4%) with aThr were all negative for other antiphospholipid antibodies. An optical density value of six of 30 patients (20.0%) with aThr showed more than a 40% reduction of reactivity to thrombin with the addition of antithrombin in a dose-dependent manner. The inhibition percentage of aThr to thrombin was prominently increased to 11 of 30 (37%) along with its inhibition rate (100% at the highest) by the co-existence of heparin. Seven out of 30 patients with aThr (23.3%) showed a reduction of the optical density value with the addition of hirudin. Our findings suggest that aThr exists solely in patients with systemic lupus erythematosus without other antiphospholipid antibodies, and the antigenic determinants of aThr are directed to exosite I (hirudin binding site) and exosite II (antithrombin/heparin binding site) on the thrombin surface, with exosite II predominance. Accordingly, aThr could be an isolated and additional new marker of thrombosis/hemostasis. Since our patients who were positive only for aThr do not have a past history of antiphospholipid-associated complications at this stage, however, further long-term follow-up and additional studies in these clinical settings are needed to verify our hypothesis in the future.     

Negligible synergistic effect of β2-glycoprotein I on the reactivity of antioxidized low-density lipoprotein antibody to oxidized low-density lipoprotein

We conducted this study to investigate whether antioxidized low-density lipoprotein (a-oxLDL) is an antibody to cryptic and/or neo-antigen on β₂-glycoprotein I (GPI), which is introduced by binding to anionic phospholipid, similar to that of GPI-dependent anticardiolipin antibody (aCL) employing a-oxLDL ELISA. We found that no significant optical density differences existed among systemic lupus erythematosus patients, including cases with aCL and/or lupus anticoagulant positivity, before and after the addition of GPI. Our results suggest that a-oxLDL is not an antibody to denatured GPI, but rather to oxLDL. © 1996 Wiley-Liss, Inc.     

Tissue-specific augmentation of circadian PAI-1 expression in mice with streptozotocin-induced diabetes

Diabetes is associated with an excess risk of cardiac events, and the risk for infarction is partly determined by plasminogen activator inhibitor-1 (PAI-1). We found that plasma total and active PAI-1 levels increased in a circadian manner in mice with streptozotocin (STZ)-induced diabetes. Circadian expression of PAI-1 mRNA in the lung, heart, liver, and kidney increased in a tissue-specific manner. Peak to peak comparisons revealed that the mRNA expression levels increased by 1.7, 1.7, 1.2, and 1.6-fold in the heart, lung, liver, and kidney, respectively. In contrast, the circadian expression of the clock gene, mPer2, was preserved in the diabetic mice, suggesting that the altered expression of PAI-1 mRNA did not arise due to impaired circadian clocks. Our results suggest that impairment of the coagulation and fibrinolytic systems induced by diabetes is partly due to impaired circadian PAI-1 fluctuation at the level of mRNA expression.