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PubMed1995

Characterization of binding of human beta 2-glycoprotein I to cardiolipin.

beta 2-Glycoprotein I-cardiolipin complexes are reported to be a target antigen for the binding of a subset of anti-phospholipid antibodies. The characteristics of binding of beta 2-glycoprotein I to cardiolipin are reported in this paper. Binding at neutral pH is specific, saturable, dependent on ionic strength and independent of bivalent cation. Binding at low pH is qualitatively different from that at neutral pH, and is not dependent on ionic strength. Denaturation of beta 2-glycoprotein I by heat inactivation and reduction/alkylation indicates that beta 2-glycoprotein I-cardiolipin interaction does not require the native three-dimensional structure of beta 2-glycoprotein I, implying that a linear sequence motif may be responsible. Modification of amino acid residues by KCNO treatment completely destroys binding capacity, indicating crucial involvement of lysine residues in binding of beta 2-glycoprotein I to cardiolipin. Complement factor H, which has some similar highly charged linear sequence motifs to beta 2-glycoprotein I and is composed of the same type of protein module, was found to bind to cardiolipin and inhibit the binding of beta 2-glycoprotein I to cardiolipin. Three different lysine-rich segments of the fifth domain of beta 2-glycoprotein I may be involved in binding to cardiolipin.

Amino Acid Sequence↗

PubMed1997

Cardiolipin is not essential for the growth of Saccharomyces cerevisiae on fermentable or non-fermentable carbon sources.

Cardiolipin is a unique dimeric phospholipid, which is present throughout the eukaryotic kingdom and is specifically localized in mitochondrial membranes. It is widely believed that mitochondria possess an essential requirement for this phospholipid. To determine whether cardiolipin is essential for yeast growth, we generated a cardiolipin synthase null mutant by disrupting the CLS1 gene (open reading frame YDL142c on chromosome IV) of Saccharomyces cerevisiae. Biochemical analysis of the mutant indicated that it had no cardiolipin synthase activity and no cardiolipin in its membranes. The enzyme phosphatidylglycerolphosphate synthase, which catalyses the committed step of the cardiolipin pathway, remained unaffected in the null mutant. Haploid cells containing the null allele are viable in media containing glucose, galactose or glycerol/ethanol as the sole carbon source, although growth in galactose or glycerol/ethanol is somewhat reduced in the mutant compared with the wild type. These results indicate that cardiolipin is not essential for the growth of S. cerevisiae in fermentable or non-fermentable carbon sources.

Amino Acid Sequence↗

PubMed2005

Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria.

Digitonin extracts of mitochondria from cardiolipin-containing (wild type) and cardiolipin-lacking (crd1Delta mutant) Saccharomyces cerevisiae subjected to colorless native polyacrylamide gel electrophoresis in the presence of 0.003% digitonin displayed a supercomplex composed of homodimers of complexes III and IV in the former case but only the individual homodimers in the latter case. To avoid treatment with any detergent or dye, we compared organization of the respiratory chain in intact mitochondria from wild type and cardiolipin-lacking cells by using a functional analysis developed previously for the study of the organization of the respiratory chain of S. cerevisiae (Boumans, H., Grivell, L. A., and Berden, J. A. (1998) J. Biol. Chem. 273, 4872-4877). Dependence of the kinetics of NADH oxidation via complexes III, IV, and cytochrome c on the concentration of the complex III-specific inhibitor antimycin A was studied. A linear relationship between respiratory activity and saturation of complex III with antimycin A was obtained for wild type mitochondria consistent with single functional unit kinetics of the respiratory chain. Under the same conditions, cardiolipin-lacking mitochondria displayed a hyperbolic relationship indicating cytochrome c pool behavior. No release of cytochrome c from cardiolipin-lacking mitochondria or mitoplasts under our standard experimental conditions was detected. Identical cytochrome c pool behavior was observed for both wild type and cardiolipin-lacking mitochondria in the presence of a chaotropic agent, which disrupts the interaction between respiratory complexes. The results demonstrate that cardiolipin is essential for association of complexes III and IV into a supercomplex in intact yeast mitochondria.

Antimycin A↗

PubMed2002

Preservation of cardiolipin content during aging in rat heart interfibrillar mitochondria.

Aging selectively decreases the rate of oxidative phosphorylation in the interfibrillar population of cardiac mitochondria (IFM) located between the myofibers. In contrast, subsarcolemmal mitochondria (SSM), located below the plasma membrane, remain unaffected. IFM from elderly (24-month-old) Fischer 344 rats have a decreased specific activity of complexes III and IV. Complexes III and IV require an inner mitochondrial membrane lipid environment enriched in the oxidatively sensitive phospholipid cardiolipin for maximal activity. We asked if aging decreases the content or alters the composition of cardiolipin as a potential mechanism of the aging defect in IFM. The content and composition of mitochondrial phospholipids were measured in SSM and IFM from adult and aging rat hearts. Aging did not alter the content of mitochondrial phospholipids, including cardiolipin, in either population of mitochondria. The composition of cardiolipin based on characterization of both acyl group and the individual molecular species of cardiolipin was also unaltered by aging. Lipid-mediated oxidative modification of complex III subunits was not detected, making cardiolipin-derived oxidative damage to complex III unlikely. Thus, alterations in cardiolipin are not the mechanism for the aging defect in IFM in Fischer 344 rats.

Aging↗

PubMed1998

Effect of glycerol on the affinity of DnaA protein for ATP in the presence of cardiolipin.

Acidic phospholipids, such as cardiolipin, decrease the affinity of DnaA protein for adenine nucleotides and can activate the inactive form of DnaA protein in vitro. In this study, we examined the effect of glycerol on the affinity of DnaA protein for ATP in the presence of cardiolipin. High concentrations of glycerol (34%) restored the affinity of DnaA protein for ATP, which was decreased by cardiolipin. Glycerol inhibited the binding of cardiolipin with DnaA protein. Glycerol had little effect on membrane fluidity, which is essential for the interaction between cardiolipin and DnaA protein, whereas it increased the Kd value of DnaA protein for ATP in the absence of cardiolipin. These results suggest that glycerol causes DnaA protein to become insensitive as to the interaction with cardiolipin by changing the conformation of the protein without altering the physical nature of the phospholipid.

Adenosine Triphosphate↗

PubMed1988

Specific binding of mitochondrial protein precursors to liposomes containing cardiolipin.

In vitro synthesized precursors of several mitochondrial proteins, including P-450(SCC), adrenodoxin, and malate dehydrogenase, bound to liposomes prepared from mitochondrial phospholipids, but not to those from microsomal phospholipids. When liposomes were prepared from various pure phospholipids, adrenodoxin precursor was bound only to the liposomes that contained cardiolipin. The liposomes containing other phospholipids did not show the binding affinity for the precursor. The binding was observed only with the precursor peptides of adrenodoxin and malate dehydrogenase, and their mature forms were not bound to the liposomes. The binding of the precursors was dependent on the concentration of cardiolipin in the liposomes. Liposomes containing various cardiolipin derivatives with modified polar head groups showed very different binding affinity for adrenodoxin precursor, suggesting the importance of the structure of the polar head of the cardiolipin molecule. Two or three positively charged amino acid residues in the extension peptide of P-450(SCC) precursor were replaced by neutral amino acid residues by site-directed mutagenesis. The mutated P-450(SCC) precursors did not bind to the liposomes containing cardiolipin. The results indicated that mitochondrial protein precursors have specific affinity for cardiolipin, and the affinity was due to the interaction between the extension peptides of the precursors and the polar head of the cardiolipin molecule.

Adrenodoxin↗

PubMed1975

Observations on lipid composition with particular reference to cardiolipin of rat heart after feeding rapeseed oil.

The influence of dietary rapeseed oil on the lipid classes and fatty acid pattern of rat heart homogenate and mitochondria has been investigated after feeding a diet with 9.8 weight- % erucic acid for 10 days and 1.4 and 2.6% erucic acid for 28 days. The rats treated with 9.8% erucic acid showed a significant increase in the triglycerides of the heart mitochondria. This tendency was much less pronounced in rats treated with 1.4 resp. 2.6% erucic acid. These results confirm those of other investigators. A slight increase in the cholesterol esters of the mitochondria could be seen in all the treated rats. The total phospholipids were decreased in the experiment with 9.8% erucic acid and slightly increased in experiments with 1.4 and 2.6% erucic acid. The concentration of phosphatidylcholine showed a tendency to increase and the concentration of phosphatidylethanolamine to decrease in the experiment with 9.8% erucic acid in the diet. The concentration of cardiolipin was mainly unchanged. In all experiments the triglycerides of the heart mitochondria showed a high content of erucic acid. The fatty acids of the cholesterol esters of the heart mitochondria were also influenced of dietary rapeseed oil but to a less extent than the triglycerides. The fatty acids of phosphatidylcholine, phosphatidylethanolamine and cardiolipin were all influenced by the dietary rapeseed oil, but the erucic acid seemed to have a specific affinity to cardiolipin. Cardiolipin of rat heart mitochondria was isolated and identified with gas chromatography and mass spectrometry. The isolated cardiolipin was found to contain 12 per cent erucic acid after feeding 9.8% erucic acid as rapeseed oil for 10 days. Similar results were obtained after feeding glyceryl trierucate for 5 days to rats. The incorporation of erucic acid into cardiolipin was followed by a corresponding decrease of linoleic acid. This observation is of great interest because the molecular structure of fatty acids in lipid molecules has a profound influence of the packing of these molecules in a bilayer. Since cardiolipin is a component of the inner membrane of mitochondria its high affinity for erucic acid might influence the normal function of the inner membrane of heart mitochondria.

Animals↗

PubMed1995

Interactions and molecular structure of cardiolipin and beta 2-glycoprotein 1 (beta 2-GP1).

beta 2-GP1 is a serum protein which influences binding of anticardiolipin antibodies to cardiolipin, may influence induction of these antibodies in animals and may play a role in anticardiolipin-mediated thrombosis. Various investigators have proposed that when beta 2-GP1 binds cardiolipin, structural alterations occur in one or both molecules, resulting in exposure of new epitopes for anticardiolipin binding, but there has been no proof that such alterations occur. Utilizing Fourier transform infrared spectroscopy, this study analysed the structure of cardiolipin and beta 2-GP1 alone, then mixed with each other. For pure cardiolipin, analysis of the CH2 stretching, scissoring and carbonyl bands suggested this molecule assumes a hexagonal crystal lattice packing structure in both anhydrous and aqueous samples. Based on the second derivative analysis of the amide 1 band from the beta 2-GP1 protein backbone, as well as Fourier self-deconvolution and curve fit algorithms, beta 2-GP1 was calculated to contain 18% turns, 37% alpha-helix, and 45% beta-sheet structure. beta 2-GP1 binding with cardiolipin results in a significant change in the conformation as well as geometry of the lipid and protein components. This is indicated by a broadening of the CH stretching band and a marked shift in intensity of the carbonyl band of cardiolipin, indicating less hydrogen bonding. There was a decrease in beta-sheet structure of beta 2-GP1 from 46% to 23% and appearance of 26% to 28% random structure. These findings indicate that mixing beta 2-GP1 with cardiolipin results in profound changes in both molecules which might explain the effect of beta 2-GP1 on anticardiolipin binding activity.

Amides↗

PubMed1993

Mitochondrial cardiolipin in diverse eukaryotes. Comparison of biosynthetic reactions and molecular acyl species.

Cardiolipin, a unique dimeric phospholipid of bacteria and mitochondria, can be synthesized by two alternative pathways discovered in rat and Escherichia coli, respectively. In mitochondrial preparations from fungi (Saccharomyces cerevisiae, Neurospora crassa), higher plants (Phaseolus aureus), molluscs (Mytilus edulis) and mammals (rat liver, bovine adrenal gland), cardiolipin was synthesized from CDP-diacylglycerol and phosphatidylglycerol, suggesting a common eukaryotic mechanism of cardiolipin formation which is in contrast to the prokaryotic biosynthesis from two molecules of phosphatidylglycerol. All mitochondrial cardiolipin synthases were inhibited by lysophosphatidylglycerol, were insensitive to N-ethylmaleimide and required divalent cations, although they had different cation specificities. The molecular species of cardiolipin from rat liver, bovine heart, S. cerevisiae and N. crassa were analysed by high-performance liquid chromatography of the derivative 1,3-bis[3'-sn-phosphatidyl]-2-benzoyl-sn-glycerol dimethyl ester. Cardiolipins from these organisms contained mainly monounsaturated or diunsaturated chains with 16 or 18 carbon atoms, resulting in a relatively homogeneous distribution of double bonds and carbon numbers among the four acyl positions. About half of the molecular species were symmetrical, i.e. they combined two identical diacylglycerol moieties. In N. crassa, the same species pattern was found at growth temperatures of 25 degrees C and 37 degrees C. Tentative molecular models were created for the most abundant molecular species and subjected to energy minimization. Geometric data, derived from these models, suggested similarities in the gross structure of the major cardiolipin species from different sources.

Adrenal Glands↗

PubMed1975

Inhibition of cardiolipin synthesis by end-products and other complex lipids in membrane preparations of Micrococcus lysodeikticus.

Using membrane preparations of Micrococcus lysodeikticus, the end-products of cardiolipin synthesis, cardiolipin and glycerol, were shown to inhibit cardiolipin synthetase at several concentrations. Other phospholipids tested for inhibitory effects, phosphatidyl-ethanolamine, phosphatidylinositol, and phosphatidic acid were also shown to inhibit cardiolipin synthesis. Phosphatidic acid was considerably more inhibitory than cardiolipin, phosphatidylethanolamine was similar to cardiolipin, and phosphatidylinositol less inhibitory at the same concentrations. A non-phosphate-containing glycolipid was also inhibitory. In contrast, glycerophosphate had no effect on cardiolipin synthesis.

Cardiolipins↗

PubMed1989

Cardiolipin-sensitive phospholipase C in subcellular fractions of rabbit myocardium.

Phosphatidylinositol-specific phospholipase C was characterized in the soluble phase and in membrane fractions prepared from rabbit myocardium. Four subforms of soluble phospholipase C were identified and characterized. Activity of one subform was inhibited 80% when cardiolipin was present in substrate vesicles, whereas three subforms were stimulated 2- to 10-fold by cardiolipin. A cationic subform, molecular mass 67 kDa, was stimulated threefold when cardiolipin comprised 2% of the total phospholipid and fivefold when it comprised 12%. The major mechanism for the cardiolipin effect was a decrease in the apparent Michaelis constant (Km) of this subform for substrate. Competition experiments were consistent with binding of this subform to cardiolipin. Phospholipase C activity was present in mitochondrial, microsomal, and sarcolemmal membrane fractions that were essentially free of contamination by cytosol. Detection of membrane-associated phospholipase C was facilitated by cardiolipin. Thus rabbit myocardium contains multiple subforms of soluble phospholipase C that differ substantially in surface charge, molecular mass, and sensitivity to cardiolipin. Anionic phospholipids may be important determinants of intracellular distribution of phospholipase C in myocardial tissue.

Animals↗

PubMed1988

Cardiolipin activation of dnaA protein, the initiation protein of replication in Escherichia coli.

ATP binding to dnaA protein is essential for its action in initiating the replication of plasmids that bear the unique origin of the Escherichia coli chromosome (oriC). ADP bound to that site renders dnaA protein inactive for replication. Diphosphatidylglycerol (cardiolipin), a diacidic membrane phospholipid, displaces the bound nucleotide, and in the presence of components that reconstitute replication, fully reactivates the inert ADP form of dnaA protein. The monacidic phosphatidylglycerol is one-tenth as active as cardiolipin, whereas the neutral phosphatidylethanolamine, the principal E. coli phospholipid, is inactive. Fluphenazine, a tranquilizer drug, blocks cardiolipin activation of dnaA protein, in keeping with the inhibitory action of such agents on phospholipid-dependent enzymes. With the use of this drug to terminate cardiolipin action, dependence of the activation on time, elevated temperature, and high levels of ATP was demonstrated. Cardiolipin binding of nucleotide-free dnaA protein prevents binding of ATP and initiation of oriC replication. Removal of a fatty acid from cardiolipin by phospholipase A reverses this inhibitory effect. The strong and specific interaction of cardiolipin, a cell membrane component, with an essential nucleotide-binding site of dnaA protein, the protein essential for the initiation of chromosome replication, may be an important element in regulating the cell cycle.

Adenosine Diphosphate↗

PubMed1986

Evaluation of the cross-reaction between anti-DNA and anti-cardiolipin antibodies in SLE and experimental animals.

The cross-reaction between anti-DNA and anti-cardiolipin IgG antibodies and its relation to the standard test for syphilis was studied with sera and monoclonal antibodies derived from human patients and mice with systemic lupus erythematosus (SLE). Syphilitic sera of humans and rabbits infected with the spirochete Treponema pallidum were also tested in this study. In addition, rabbits were immunized with ssDNA and cardiolipin and the cross-reactions of the induced antibodies were studied in two different assay systems. The results of these experiments suggest: that the anti-DNA and anti-cardiolipin IgG autoantibodies in SLE sera constitute separate antibody populations and, therefore, cardiolipin cannot play a role in the induction of immune response to DNA in SLE; that in immunized experimental animals there is a significant level of cross-reaction between anti-DNA and anti-cardiolipin-the detection of this cross-reaction depends on highly amplified solid phase assay systems which measure low affinity antibodies and that there is no correlation between the activity of syphilitic sera in the serologic test for syphilis and their binding to pure cardiolipin-this implies that cardiolipin may not be the dominant ingredient in this test as previously proposed.

Animals↗

PubMed1985

Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes.

Doxorubicin possesses high affinity for binding to cardiolipin. We have utilized these properties in preparing stable liposomes of doxorubicin and cardiolipin with a net positive charge. Doxorubicin liposomes were formed by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. These liposomes were sonicated for 90 min at 37 degrees followed by extensive dialysis against buffer. The pharmacological, toxicological, and therapeutic effects of doxorubicin entrapped in cardiolipin liposomes were compared with those of free doxorubicin in mice. At a dose of 4 mg/kg i.v., the peak cardiac concentration was achieved in 30 min following free doxorubicin administration, the value being 8.1 micrograms/g. The peak cardiac concentration with doxorubicin in cardiolipin liposomes was obtained at 5 min with a value of 2.8 micrograms/g of tissue. The cardiac concentration X time values for free doxorubicin for the 24-hr period of observation were 55.1 micrograms X hr/g, whereas it was only 7.8 micrograms X hr/g with the drug entrapped in cardiolipin liposomes. Compared to free drug, the liposomal entrapped doxorubicin significantly reduced the histopathological lesions in cardiac tissue of mice at a dose of 15 mg/kg as determined by electron microscopy. The nadir of peripheral white blood cell counts in mice with free drug, 6 mg/kg, was observed on Day 3 which was 50% of control, whereas with liposomal encapsulated drug it was reduced only 23% on Day 7. Doxorubicin in cardiolipin liposomes demonstrated enhanced chemotherapeutic potential against murine ascitic P388 leukemia with a 144% increased life span compared to 55% increased life span with free drug at a dose of 7.5 mg/kg on Days 1, 3, and 7. We conclude that doxorubicin liposomes developed in these studies possess improved therapeutic action as demonstrated by their ability to reduce the toxicity of the drug substantially.

Animals↗

PubMed1993

On the reversal by deoxyribonucleic acid of the binding of adriamycin to cardiolipin-containing liposomes.

The binding of the cytotoxin adriamycin (doxorubicin) to phospholipids, DNA, and RNA was investigated using (i) fluorescence quenching by this drug of liposomes containing pyrene-labeled phospholipids and (ii) monomolecular cardiolipin films on an air/water interface. In accordance with previous studies, our fluorescence experiments revealed that the acidic phospholipids, phosphatidylglycerol, phosphatidylmethanol, and phosphatidic acid all have high and comparable affinities to adriamycin mainly due to electrostatic interactions whereas binding to phosphatidylcholine was much weaker. Highest affinity, however, was possessed by cardiolipin. Addition of 4 mM CaCl2 reduced the binding of adriamycin to the above lipids. Moreover, in the presence of calcium the affinity of the drug to the different lipids was similar. Ca2+ concentrations > 100 microM began to reverse the binding of adriamycin to cardiolipin-containing liposomes whereas lower concentrations had only an insignificant effect. The association of adriamycin with DNA, RNA, and cardiolipin was then compared by observing the reversal of the cytotoxin-cardiolipin association by nucleic acids. The affinity of adriamycin was found to decrease in the sequence DNA > cardiolipin > RNA with relative affinities of 7.8, 2.3, and 1, respectively. Penetration of the drug into cardiolipin monolayers spread on an air/water interface resulted in an increase in surface pressure pi whereas only a very weak increase was observed using dimyristoylphosphatidylcholine films. Removal of adriamycin from lipid monolayers was achieved by adding DNA into the aqueous subphase. Similar to the fluorescence quenching studies increase in pi after the inclusion of adriamycin into the aqueous subphase was significantly reduced in the presence of Ca2+ concentrations > 100 microM, whereas lower concentrations had only an insignificant effect. Residual drug-phospholipid interactions in the lipid monolayer observed in the presence of Ca2+ were also reversed by DNA.

Binding Sites↗

PubMed1998

On the mechanism of the phospholipase C-mediated attenuation of cardiolipin biosynthesis in H9c2 cardiac myoblast cells.

The effect of phospholipase C treatment on cardiolipin biosynthesis was investigated in intact H9c2 cardiac myoblasts. Treatment of cells with phosphatidylcholine-specific Clostridium welchii phospholipase C reduced the pool size of phosphatidylcholine compared with controls whereas the pool size of cardiolipin and phosphatidylglycerol were unaffected. Pulse labeling experiments with [1,3-3H]glycerol and pulse-chase labeling experiments with [1,3-3H]glycerol were performed in cells incubated or pre-incubated in the absence or presence of phospholipase C. In all experiments, radioactivity incorporated into cardiolipin and phosphatidylglycerol were reduced in phospholipase C-treated cells with time compared with controls indicating attenuated de novo biosynthesis of these phospholipids. Addition of 1,2-dioctanoyl-sn-glycerol, a cell permeable 1,2-diacyl-sn-glycerol analog, to cells mimicked the inhibitory effect of phospholipase C on cardiolipin and phosphatidylglycerol biosynthesis from [1,3-3H]glycerol indicating the involvement of 1,2-diacyl-sn glycerol. The mechanism for the reduction in cardiolipin and phosphatidylglycerol biosynthesis in phospholipase C-treated cells appeared to be a decrease in the activities of phosphatidic acid:cytidine-5'triphosphate cytidylyltransferase and phosphatidylglycerolphosphate synthase, mediated by elevated 1,2-diacylsn-glycerol levels. Upon removal of phospholipase C from the incubation medium, phosphatidylcholine biosynthesis from [methyl-3H]choline was markedly stimulated. These data suggest that de novo phosphatidylglycerol and cardiolipin biosynthesis may be regulated by 1,2-diacyl-sn-glycerol and support the notion that phosphatidylglycerol and cardiolipin biosynthesis may be coordinated with phosphatidylcholine biosynthesis in H9c2 cardiac myoblast cells.

Animals↗

PubMed1996

Affinity-purified cardiolipin-binding antibodies show heterogeneity in their binding to oxidized low-density lipoprotein.

Antiphospholipid antibodies in autoimmune sera have been shown to react with a complex of phospholipids (cardiolipin) and a plasma phospholipid-binding protein, beta 2-glycoprotein I (apolipoprotein H). The binding of these antibodies was inhibited by oxidized low-density lipoprotein (LDL) in sera from patients with systemic lupus erythematosus (SLE), suggesting cross-reactivity between antiphospholipid antibodies and antibodies binding to oxidized LDL. We purified antiphospholipid antibodies by cardiolipin-polyacrylamide column from seven SLE sera and studied the reactivity of eluted fractions with cardiolipin-beta 2-glycoprotein I complex and oxidized LDL (malondialdehyde-conjugated LDL) in solid-phase enzyme immunoassay. In four sera the binding of IgG antibodies to cardiolipin-beta 2-glycoprotein I complex and to oxidized LDL appeared in the same fractions, whereas in three sera reactivities against cardiolipin and oxidized LDL were observed, at least in part, in separate fractions. The binding to solid-phase cardiolipin was dependent on the presence of exogenous beta 2-glycoprotein I in all fractions. Our findings show that antiphospholipid antibodies are heterogeneous in their binding to oxidized LDL, indicating that these two antibodies may have different subspecificities. Some eluted fractions reacted only with oxidized LDL, and did not show binding to cardiolipin-beta 2-glycoprotein I complex, suggesting that the lipid part in the antigenic complex might be responsible for the cross-reactivity of these antibodies. Accordingly, the biological functions of antibodies against phospholipid-beta 2-glycoprotein I complex and antibodies against oxidized LDL may also be different.

Adult↗

PubMed1996

Thrombogenic properties of murine anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies.

BACKGROUND: Recurrent arterial thrombosis and venous thrombosis are frequent complications of the antiphospholipid syndrome (APS). Patients produce anti-cardiolipin antibodies, but the role of these antibodies in thrombus formation is uncertain. This study used a unique CD-1 mouse model of thrombosis to determine whether anti-cardiolipin and anti-beta 2 glycoprotein 1 (beta 2 GP1) antibodies induced immunologically in these animals are thrombogenic. METHODS AND RESULTS: The CD-1 mouse model enables measurement of the kinetics of a thrombus induced in the femoral vein of the animal. Animals are first anesthetized, then one femoral vein is exposed and subjected to a standardized, nonpenetrating "pinch" injury that induces a thrombus. The vein is trans-illuminated, and the growing thrombus is visualized on a television screen. The rate of formation and disappearance of the thrombus as well as its area can be measured by a computer attached to the television. Three groups of CD-1 mice (each group comprising seven animals) were studied. Group 1 mice were actively immunized with beta 2GP1, resulting in production of anti-beta 2GP1 and anti-cardiolipin antibodies. Group 2 mice were actively immunized with human immunoglobulin G (IgG) anti-cardiolipin antibodies and produced anti-human IgG as well as anti-cardiolipin antibodies (the latter by an idiotype-anti-idiotype reaction). These animals did not produce anti-beta 2GP1 antibodies. Group 3 mice were immunized with human serum albumin (HSA) and produced anti-HSA but not anti-cardiolipin antibodies. The kinetics of thrombus formation induced in the femoral veins of the experimental mice were compared. Results showed that the mean thrombus area as well as mean time during which thrombi persisted were significantly greater in group 1 and group 2 mice compared with group 3. There was no statistical difference between group 1 or group 2. CONCLUSIONS: Demonstration of a thrombogenic effect of murine anti-cardiolipin antibodies suggests that these antibodies may be pathogenic in humans with APS.

Animals↗