Biomedical subjects

L Asatryan

Publications and source records attributed to L Asatryan.

4 recordsLinked to original sources

PubMed2001

Differential role of cytosolic phospholipase A2 in the invasion of brain microvascular endothelial cells by Escherichia coli and Listeria monocytogenes.

Invasion of brain microvascular endothelial cells (BMECs) is a key step in the pathogenesis of meningitis due to Escherichia coli and Listeria monocytogenes. Although host cell actin cytoskeletal rearrangements are essential in BMEC invasion by E. coli K1 and L. monocytogenes, the underlying signaling mechanisms remain unclear. This study demonstrates that host cell cytosolic phospholipase A2 (cPLA2) contributes to E. coli K1 invasion of BMECs but not to L. monocytogenes invasion of BMECs. This difference was observed with 4-bromophenacyl bromide, a nonselective PLA2 inhibitor, and arachidonyl trifluoromethyl ketone, a selective cPLA2 inhibitor, and was confirmed with BMEC derived from cPLA2 knockout mice. Activation of cPLA2 leads to generation of intracellular arachidonic acid, which is metabolized via cyclooxygenase (COX) and lipo-oxygenase (LOX) pathways into eicosanoids. COX and LOX inhibitors also significantly inhibit E. coli K1 invasion of BMECs.

Alkaloids↗

PubMed1999

Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood. Relevance to atherogenesis caused by hemodialysis.

Human blood contains a form of minimally modified low density lipoprotein (LDL), termed LDL-, whose origin remains unknown. Exploring the mechanism of formation, we found that LDL- can be produced in plasma in the absence of oxygen following LDL incubation with oxidized hemoglobin species. A high degree of apolipoprotein B100 modification results from covalent association of hemoglobin with LDL involving dityrosine formation but not due to the malonaldehyde epitope formation. This was evidenced by the cross-reactivity of oxidized LDL with antibodies against hemoglobin that was accompanied by a 60-fold increase in dityrosine levels. In this study we found significantly higher LDL- levels in the blood of hemodialysis patients, perhaps contributing to their greatly increased risk of atherosclerosis. The mechanism of LDL- formation was studied during ex vivo blood circulation using a model system resembling clinical hemodialysis in terms of the induction of inflammatory responses. This circulation increased free hemoglobin and LDL- levels compared with non-circulated blood without appreciable lipid peroxidation. Pronounced increases in LDL- were found also during circulation of plasma supplemented with nanomolar hemoglobin levels. The increase in dityrosine content and presence of heme in LDL after blood circulation suggest that LDL is modified, in part, by hemoglobin-LDL conjugates containing heme. Thus, hemoglobin-mediated reactions leading to LDL oxidation in plasma can account for high LDL- levels in hemodialysis patients.

Adult↗

PubMed1999

Low density lipoprotein (LDL) modification: basic concepts and relationship to atherosclerosis.

A large number of clinical studies support the hypothesis that the risk for atherosclerosis is associated with the proportion of different LDL subfractions in blood. Electronegatively modified forms of LDL (LDL(-)) isolated using different chromatographic techniques are characterised by significant differences in the protein and lipid content as compared to the native LDL subfraction. LDL(-) composition appears to influence its atherogenic properties as well as its high susceptibility to oxidation and impaired metabolism. Increased LDL(-) levels are found in subjects with coronary artery disease, particularly in diabetics and patients undergoing haemodialysis (HD). Whether elevated LDL(-) levels are due to the LDL oxidation in blood remains disputed despite the oxidative character of LDL(-) modification. Plausible means for LDL(-) formation in blood include glycation and protein-radical interactions with ApoB 100. The latter can prevail during HD as observed in in vitro studies using a model HD system. The rapid and progressive formation of LDL(-) during standard HD can be significantly reduced employing haemolipodialysis (HLD), which provides local delivery of specific antioxidants (vitamin E and C) to blood at concentrations above normal physiologic levels. This procedure appears to be more effective than oral supplementation with antioxidants and may be a promising approach to reducing the rapid progression of atherosclerosis in HD patients.

Animals↗

PubMed1999

Oxidative stress resulting from hemolysis and formation of catalytically active hemoglobin: protective strategies.

OBJECTIVES: The possible oxidative complications induced by free hemoglobin (Hb) released during the blood storage are discussed together with therapeutic strategies using vitamin E and specific inhibitor haptoglobin. Prooxidative properties of Hb in blood have been examined using LDL as a marker for oxidative stress, which contribute to toxicity observed in a number of pathologies aggravated by hemolysis or hemorrhagic lesions as well as after the transfusion of stored blood. MATERIALS: Experiments were performed using fresh blood or stored blood that was obtained from a blood bank on the day corresponding to the identified expiration date. METHODS: Oxidation of LDL was determined by means of the formation of mildly oxidized LDL (LDL-) using anion exchange chromatography. Concentrations of Hb were determined spectrophotometrically. RESULTS: Hb-mediated oxidative processes in cellular membranes have been well documented over the past decade. We showed that catalytic activity of Hb released during blood storage was sufficient to increase the proportion of LDL- fraction in blood after 4 h incubation at 37 degrees C. The intensity of this oxidative process as well as the release of Hb varied in different donors and may depend on the antioxidant capacity of blood. Accumulation of Hb during storage was significantly decreased in range of 15 - 32% in blood supplemented with low concentrations of alpha-, gamma-tocopherols. Similar effects were observed in the presence of low concentrations of haptoglobin, which has been reported as a specific inhibitor of hemoglobin-mediated oxidation. CONCLUSIONS: The specific inhibition of hemoglobin-mediated oxidation in lipoproteins and cellular membranes may improve the quality of stored blood and help to decrease complications arising from oxidative stress after transfusions or during hemolytic events. Based on growing evidence for a role of oxidatively modified LDL in atherosclerosis, hemolytic pathologies should receive further consideration as risk factors for cardiovascular disease.

Blood↗