[LDL oxidation and uptake by monocyte-derived macrophages from blood of patients with ischemic heart disease].

The aim of this study was to test our hypothesis that monocyte-derived macrophages of patients with ischemic heart diseases (IHD, MPIHD) were prestimulated (primed) or stimulated cells whose capacity for LDL oxidation and uptake exceeded that ofmacrophages from healthy donors (MPN). Monocytes were obtained from the blood of 18 healthy donors and 25 IHD patients; plasma LDL--from 16 another group healthy donors (LDLN) and 15 patients with family hypercholesterolemia. Incubation of LDLN or LDLH with MPIHD or MPN was carried out under aerobic and hypoxic conditions. It was shown that incubation of LDLN or LDLH with MPIHD TBARS accumulation, LDL aggregation, apoB fragmentation were observed earlier and proceeded more actively than in the case of incubation with MPN. MPIHD (compared to MPN) more actively uptook LDLH and LDLN as accumulated greater amounts of total cholesterol (TCh) (by a factor of 1.8-2.1; p < 0.05-0.01), and their viability decreased to a markedly greater degree (p < 0.01). MPIHD and MPN also oxidized and took up LDLH with a higher intensity than LDLN, and their capacity for LDL oxidation and uptake increased, under hypoxic condition, compared to those under aerobic conditions. Thus, new experimental results provide direct evidence that macrophages of IHD patients are in vivo priming or stimulated cells and that this stimulation, especially in combination with hypercholesterolemic LDL and hypoxia, is a very strong risk factor that can predispose these patients to the onset or progression of atherosclerosis. Using MPIHD, it was created express-method for evaluation the degree of monocyte/macrophage stimulation in patients with IHD, selection of premedication medicine and new antiatherosclerotic and antiischemic drugs.

Effect of antioxidant probucol on cell-mediated LDL oxidation in vitro and in vivo.

We studied the effect of phenol antioxidant probucol on free radical oxidation of LDL isolated from blood plasma of healthy donors. Oxidation was induced by co-incubation of LDL with cultured peripheral blood monocyte-macrophages and human umbilical vein endothelial cells under conditions of ischemia-reperfusion. In addition, the effect of probucol therapy on oxidability of plasma LDL in CHD patients was examined. Probucol (0.1-10 microM) efficiently protected LDL from free radical oxidation in vitro and in vivo.

Tumor necrosis factor-alpha in low doses preactivates and activates macrophages by increasing their ability to produce reactive oxygen species and oxidize low-density lipoproteins: protective effect of antioxidants.

Tumor necrosis factor-alpha in low doses activated rat peritoneal macrophages and intensified production of reactive oxygen species (zymosan-depended chemiluminescence). Single or 2-fold incubation with tumor necrosis factor-a activated and preactivated human blood macrophages and promoted oxidative modification of low-density lipoproteins (increased their mobility in agarose gel). Antioxidants (potassium phenosan, probucol, and desferal) suppressed oxidative modification of low-density lipoproteins induced by nonactivated, preactivated, and activated macrophages. Our results show that antioxidants hold much promise for the prevention and therapy of atherosclerosis.

[The use of antioxidants and antihypoxants for decreasing of LDL oxidation by macrophages and endothelial cells in ischemia and reperfusion of vascular wall]. / Primenenie antioksidantov i antigipoksantov dlia snizheniia okisleniia LNP pod vliianiem makrofagov i éndotelial'nykh kletok v usloviiakh ishemii i reperfuzii sosudistoi stenki.

Oxidative modification of LDL is a key factor in pathogenesis of atheroslerosis. In this work the effects of antioxidants (K-phenosan, probucol, and desferal) and antihypoxants (succinic acid, hypoxen, and deltaran) on the macrophage- and endothelial cell-mediated oxidation of LDL was studied. Electrophoretic mobility of LDL, the content of lipid peroxide products (TBARS and diene conjugates, DC) and cell viability were used as the indexes of LDL oxidation. The effectiveness of antioxidants as inhibitors of LDL oxidation decreased in the following order: desferal > probucol > K-phenosan, and antihypoxant ability was decreased in line: deltaran >> succinic acid (effect only in dose 40 mg/ml) >> hypoxane (no effect). The effect antioxidants on protection of cell viability (MP and EC) during ischemia reduced in the same order. The effectiveness of antihypoxant protection of MP viability, decreased in the following order: succinic acid > hypoxen >> deltaran. Macrophages added to 24 h ischemized EC + LDL in early reperfusion period decreased LDL EPM. This may apparently be attributed to selective uptake of oxidized LDL by MP.