Central Illustration. Pathophysiological pathways providing a causal link between high plasma concentrations of lipoprotein(a) (Lp(a)) and atherosclerotic vascular disease and aortic valve stenosis (AVS). Clinical outcomes are related to accelerated atherosclerosis complicated by atherothrombosis (myocardial infarction, stroke), peripheral artery disease (PAD) or aortic valve replacement (AVR) caused by valve calcification and aortic stenosis. Apo(a): apolipoprotein(a); LDL: low-density lipoprotein; OxPL: oxidized phospholipids; NSFA: Nouvelle Société Francophone d’Athérosclérose; SP: serine-protease domain; V: plasminogen kringle V (reproduced with permission).相似文献
The intercellular adhesion molecule 1 (ICAM-1) on endothelial cells is involved in the recruitment of leukocytes to inflammatory
sites. In contrast to ICAM-1 expression on endothelial cells, little is known about its function in leukocytes in inflammation.
Using ICAM-1-directed anti-sense oligodeoxyribonucleotides (ODNs), we examined the role of ICAM-1 expression on monocytes
and lymphocytes for adhesion and trans-endothelial migration. As determined by flow cytometry, a downregulation of the ICAM-1
expression of 50 % was observed on peripheral blood mononuclear cells (PBMCs) after their transfection with anti-sense ODNs
using cationic lipids. The decrease in the level of ICAM-1 expression in PBMCs was associated with a 36% inhibition of adhesion
to interleukin-1β-stimulated endothelial cells and a 40% reduction of trans-endothelial migration. Gating on particular subsets of the PBMC,
the downregulation of ICAM-1 and the functional effects could be ascribed to monocytes, while no significant inhibition was
found for lymphocytes. This could be explained by differences in cellular ODN uptake. Since the ligands of ICAM-1 are not
expressed on endothelial cells, the results suggest a homotypic interaction among monocytes. In conclusion, in addition to
ICAM-1 expression on endothelial cells, ICAM-1 expression on monocytes mediates adhesion and trans-endothelial migration.
This might be relevant for the clinical use of ICAM-1-directed anti-sense ODNs for the treatment of inflammatory diseases,
because monocytes appear to be suitable target cells in which to achieve anti-inflammatory effects.
Received: 25 June 1999 / Accepted: 2 December 1999 相似文献
Summary. An asialoglycoprotein-based DNA delivery system containing an antisense oligo DNA against the polyadenylation region and adjacent upstream sequences of woodchuck hepatitis virus (WHV) was prepared. Experimental woodchucks were inoculated neonatally with the woodchuck virus 23 weeks before initiating the study, and all animals subsequently developed hepatitis as evidenced by the presence of measurable levels of circulating viral DNA. Animals were injected intravenously (i.v.) with asialoorosomucoid (AsOR)-poly- l -lysine complexes containing 0.1 mg kg-1 antisense DNA for five consecutive days. Levels of surface antigen did not differ substantially between treated and control animals. However, intravenous administration of complexed antisense DNA significantly decreased viraemia, as shown by a five-to 10-fold decrease in circulating viral DNA 25 days post treatment. The decline lasted for at least 2 weeks, after which there was a gradual increase in DNA levels. Antisense DNA alone or a complex containing a random oligo DNA of the same size and linkage failed to have any significant effect on viral DNA levels. We conclude that antisense oligo DNA can be targeted to the liver in vivo, resulting in a substantial and prolonged decrease in viral DNA levels in WHV-infected woodchucks. 相似文献
We have compared the antileukaemic efficacy of a series of new i.v. injectable alkylphosphocholines (APC) with their clinically used congeners miltefosine and perifosine. The test system consisted of four leukaemic cell lines carrying the bcr-abl rearrangement (K-562, LAMA-84, CML-T1 and BV-173) and two other leukaemic cell lines (HL-60 and SKW-3) without this genetic alteration. The prototype of i.v. injectable APC, erucylphosphocholine, was more active against BCR-ABL-positive cell lines than the two reference APC. It induced programmed cell death in HL-60 and SKW-3 cells after exposure for 24 h, and in bcr-abl expressing cells after a prolonged incubation period (48 h). LAMA-84 cells responded to i.v. injectable APC with increased conversion to an adherent, fibroblast-like phenotype. Experiments with a cell-free system showed that the target structures of APC are localized within the cytoplasmic compartment. Blockade of ceramide synthase by fumonisin B1 was insufficient to prevent oligonucleosomal DNA fragmentation. Using RT-PCR we confirmed that K-562 and LAMA-84 cells carry the b3a2 fusion type, and CML-T1 and BV-173 the b2a2 variant. BV-173 cells had the lowest level of bcr-abl mRNA which correlated with their increased sensitivity. Transfection of K-562 cells with antisense oligonucleotides directed against bcr-abl caused a specific suppression of K-562 clonogenicity. Our data indicated that i.v. injectable alkylphosphocholines are potent inducers of apoptosis and display increased antileukaemic efficacy against BCR-ABL-positive blasts as compared with miltefosine and perifosine. The expression of BCR-ABL cannot prevent apoptosis but delays erucylphosphocholine-induced programmed cell death. Transfection with bcr-abl directed antisense oligonucleotides reduces the clonogenicity of K-562 cells. 相似文献
