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PubMedDate not supplied

Anti-cardiolipin antibodies in HIV infection are true antiphospholipids not associated with antiphospholipid syndrome.

The aim of the present study was to evaluate the fine specificity of anticardiolipin (aCL) antibodies detectable in the sera of patients with HIV infection. aCL are generally associated with thrombotic events in autoimmune diseases. A solid phase ELISA which discriminates between aCL binding to phospholipids and aCL binding to phospholipid/beta 2-glycoprotein I (cofactor) complex was employed. Thirty-nine HIV and 20 aCL positive systemic lupus erythematosus (SLE) sera were examined. In HIV sera, reduced binding to phospholipid was seen if cofactor was added. On the contrary, in SLE-sera the cofactor improved aCL binding. No thrombotic events were recorded in HIV infected subjects presenting with aCL. Thus, aCL in HIV infection and in SLE appear to have different specificities. In HIV infection the true epitope of aCL is likely to be on the phospholipid component only, whereas in SLE aCL seem directed against the cofactor/CL complex. Considering the anticoagulant role of beta 2-glycoprotein I, this observation might account for the lack of thrombosis in HIV patients with "true" aCL.

Antibodies, Anticardiolipin↗
PubMed1996

[Serum cardiolipin antibodies in patients with alcoholic cirrhosis].

OBJECTIVE: Although portal obstruction is a complication in cirrhosis which is usually associated with hepatocellular carcinoma, its precise neoplastic or thrombotic nature is not easy to determine. Serum antiphospholipid antibodies could be involved in thrombosis-related portal obstruction. PATIENTS AND METHODS: The presence of serum anticardiolipid antibodies was investigated by an immunoenzymatic technique in 129 patients with alcoholic cirrhosis, 47 patients with hepatocellular carcinoma with (n = 18) or without (n = 29) portal obstruction, and 82 patients without hepatocellular carcinoma or portal obstruction. Five control groups were included: patients with non alcoholic cirrhosis (n = 21), non cirrhotic alcoholic liver disease (n = 21), chronic viral hepatitis (n = 14), extra-hepatic cholestasis (n = 9), and hypergammaglobulinemia associated with human immunodeficiency virus infection without liver disease (n = 28). RESULTS: The prevalence of serum anticardiolipid antibodies was 57% in patients with alcoholic cirrhosis, which was significantly different from the prevalence in the control groups which ranged from 0 to 32%. Anticardiolipid antibodies were of IgA isotypes in 90.5% of the cases, mainly related to the degree of liver failure but not to hepatocellular carcinoma or portal obstruction. CONCLUSION: In alcoholic cirrhosis, serum anticardiolipid antibodies do not seem to be related to the pathogenesis of portal obstruction in patients with hepatocellular carcinoma. They could rather reflect liver lesions and immunological dysfunctions.

Adult↗
PubMed1999

Acylation of monolysocardiolipin in rat heart.

Cardiolipin is a major mitochondrial membrane glycerophospholipid in the mammalian heart. In this study, the ability of the isolated intact rat heart to remodel cardiolipin and the mitochondrial enzyme activities that reacylate monolysocardiolipin to cardiolipin in vitro were characterized. Adult rat heart cardiolipin was found to contain primarily linoleic and oleic acids. Perfusion of the isolated intact rat heart in the Langendorff mode with various radioactive fatty acids, followed by analysis of radioactivity incorporated into cardiolipin and its immediate precursor phosphatidylglycerol, indicated that unsaturated fatty acids entered into cardiolipin mainly by deacylation followed by reacylation. The in vitro mitochondrial acylation of monolysocardiolipin to cardiolipin was coenzyme A-dependent with a pH optimum in the alkaline range. Significant activity was also present at physiological pH. With oleoyl-coenzyme A as substrate, the apparent K(m) for oleoyl-coenzyme A and monolysocardiolipin were 12.5 microm and 138.9 microm, respectively. With linoleoyl-coenzyme A as substrate, the apparent K(m) for linoleoyl-coenzyme A and monolysocardiolipin were 6.7 microm and 59.9 microm, respectively. Pre-incubation at 50 degrees C resulted in different profiles of enzyme inactivation for the two activities. Both activities were affected similarly by phospholipids, triacsin C, and various lipid binding proteins but were affected differently by various detergents and myristoyl-coenzyme A. [(3)H]cardiolipin was not formed from monolyso[(3)H]cardiolipin in the absence of acyl-coenzyme A. Monolysocardiolipin acyltransferase activities were observed in mitochondria prepared from various other rat tissues. In summary, the data suggest that the isolated intact rat heart has the ability to rapidly remodel cardiolipin and that rat heart mitochondria contain coenzyme A-dependent acyltransferase(s) for the acylation of monolysocardiolipin to cardiolipin. A simple and reproducible in vitro assay for the determination of acyl-coenzyme A- dependent monolysocardiolipin acyltransferase activity in mammalian tissues with exogenous monolysocardiolipin substrate is also presented.

Acyl Coenzyme A↗
PubMed1984

Doxorubicin inhibits the phosphate-transport protein reconstituted in liposomes. A study on the mechanism of the inhibition.

The phosphate transport protein (PTP) has been isolated from beef heart mitochondria in the presence of cardiolipin and reconstituted in asolectin and phosphatidylcholine vesicles. As expected, the activity of the reconstituted PTP is inhibited by N-ethylmaleimide and mersalyl. It is also inhibited by adriamycin and Br-daunomycin. Storage of isolated mitochondria at -80 degrees C prior to the isolation of the PTP decreases the maximal activity of the unidirectional transport of phosphate (Pi) in reconstituted vesicles. The sensitivity of the system to the four inhibitors remains the same. The inhibition of the PTP by adriamycin is reversed by KCl and prevented by MgSO4. Since the interaction between adriamycin and cardiolipin is of ionic type, KCl apparently replaces adriamycin on the negative charges of cardiolipin. By contrast, MgSO4 complexes adriamycin directly, eliminating its inhibitory effect on the PTP. No PTP activity is found after reconstitution in phosphatidylcholine vesicles in the absence of cardiolipin. Addition of buffer-dispersed cardiolipin to the vesicles restores the Pi-transport activity. The addition of adriamycin to the vesicles together with cardiolipin removes the reactivation. Succinylation of the PTP at pH 8.0 eliminates the inhibitory effect of adriamycin in the reconstituted system. The effects of N-ethylmaleimide and mersalyl are not modified. The succinylated preparation reconstituted in phosphatidylcholine vesicles is reactivated by cardiolipin, but in this case the reactivation is not counteracted by adriamycin. Succinylation of the PTP at pH 9.0 results in its complete inhibition. The results indicate, (a) that the sites of interaction of MalNEt /mersalyl and adriamycin with the PTP X cardiolipin complex are different, and (b) that the adriamycin-binding site in the complex is probably on cardiolipin molecules essential to the PTP activity. It is postulated that succinylation of the PTP prevents the interaction of adriamycin with these molecules.

Animals↗
PubMed1986

Reactivity patterns of human anticardiolipin and other antiphospholipid antibodies in syphilitic sera.

Sera from patients with proven cases of syphilis were tested for the presence of antibodies to structurally important phospholipids by using qualitative and quantitative assays. All 47 sera examined qualitatively contained antibodies to cardiolipin, phosphatidic acid, and phosphatidylserine, but not antibodies to other selected phospholipids. Such reactivity was not found in normal (Red Cross) sera. Although the degree of antibody binding to phospholipids varied in individual sera, reactivity was almost always greater with cardiolipin than with phosphatidic acid or phosphatidylserine. Binding saturability was found in sera as the cardiolipin concentration was increased over a constant area of nitrocellulose paper. Anti-cardiolipin binding measured by the protein A method gave results similar to the results measured by using anti-immunoglobulin G, which supports the conclusion that binding was to the Fab portion of the immunoglobulin molecule. When measured as a function of serum concentration and plotted in double-reciprocal fashion, the anti-cardiolipin binding data for two syphilitic sera had similar Kd values but different Bmax values. Stoichiometric calculations indicated that approximately 11,000 to 16,000 mol of cardiolipin appeared to be bound per mole of labeled second antibody. These observations may mean that the anti-cardiolipin antibody does not recognize the individual cardiolipin molecule as the antigenic site but recognizes some structural form of the phospholipid or that steric hindrance related to the interaction of the phospholipid with nitrocellulose paper prevented the bulk of cardiolipin molecules from reaching. The structural specificity of the antibodies identified excludes the possibility that these antibodies are directed against the phosphodiester linkage. These findings should give impetus to future study of a potential pathogenic or marker role for these antibodies in syphilis and in other syndromes in which membrane damage may be a primary event.

Antibodies↗
PubMed1999

N-Acetylsphingosine stimulates phosphatidylglycerolphosphate synthase activity in H9c2 cardiac cells.

Cardiolipin and phosphatidylglycerol biosynthesis were examined in H9c2 cells incubated with short-chain ceramides. Incubation of cells with N-acetylsphingosine or N-hexanoylsphingosine stimulated [1, 3-3H]glycerol incorporation into phosphatidylglycerol and cardiolipin, with N-acetylsphingosine having the greater effect. The mechanism for the ceramide-mediated stimulation of de novo phosphatidylglycerol and cardiolipin biosynthesis appeared to be an increase in the activity of phosphatidylglycerolphosphate synthase, the committed step of phosphatidylglycerol and cardiolipin biosynthesis. The presence of the potent protein phosphatase inhibitors calyculin A or okadaic acid attenuated the N-acetylsphingosine-mediated stimulation of phosphatidylglycerolphosphate synthase activity and of phosphatidylglycerol and cardiolipin biosynthesis, indicating the involvement of a ceramide-activated protein phosphatase(s). The presence of 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) stimulated enzyme activity and [1,3-3H]glycerol incorporation into phosphatidylglycerol and cardiolipin. The effects of CPT-cAMP and N-acetylsphingosine on phosphatidylglycerol and cardiolipin biosynthesis and on phosphatidylglycerolphosphate synthase activity were additive. Phosphatidylglycerol biosynthesis from sn-[14C]glycerol 3-phosphate in permeabilized H9c2 cells was stimulated by preincubation with N-acetylsphingosine, and this was attenuated by okadaic acid. N-Acetylsphingosine treatment of cells elevated mitochondrial phospholipase A2 activity. Since the pool sizes of phosphatidylglycerol and cardiolipin were unaltered in these cells, the observed increase in phosphatidylglycerolphosphate synthase activity may be a compensatory mechanism for the N-acetylsphingosine-mediated elevation of mitochondrial phospholipase A2 activity. Finally, addition of tumour necrosis factor alpha to H9c2 cells resulted in an elevation of both phosphatidylglycerolphosphate synthase and phospholipase A2 activities. The results suggest that phosphatidylglycerol and cardiolipin metabolism in H9c2 cells may be regulated by intracellular ceramide signalling.

Animals↗
PubMed2001

Antiphospholipid antibodies associated with alcoholic liver disease specifically recognise oxidised phospholipids.

BACKGROUND: Circulating antiphospholipid antibodies (aPL) are often detected in patients with alcoholic liver disease (ALD) but little is known about the causes of their formation. AIMS: We have evaluated whether ethanol mediated oxidative injury might promote the development of aPL in ALD. PATIENTS AND METHODS: IgG against beta(2) glycoprotein 1 (beta(2)-GP1), cardiolipin, and human serum albumin (HSA) complexed with either oxidised arachidonic acid (HSA-APP) or malondialdehyde (HSA-MDA) were assayed by ELISA in heavy drinkers with or without ALD and in healthy subjects. RESULTS: Circulating IgG recognising cardiolipin were significantly higher in ALD patients than in controls. However, anticardiolipin reactivity of ALD sera was only evident using, as the antigen, oxidised cardiolipin but not oxidation protected cardiolipin. In ALD patients, individual values of IgG antioxidised cardiolipin were associated with the titres of antibodies against HSA-MDA and HSA-APP (r=0.68 and 0.72, respectively; p<0.0001) used as markers of oxidative stress. ALD patients also displayed increased levels of antibodies against phospholipid binding protein beta(2)-GP1, and individual reactivity towards oxidised cardiolipin and beta(2)-GP1 were highly correlated (r=0.85; p<0.0001). IgG binding to oxidised cardiolipin, HSA-MDA, and HSA-APP was also significantly higher in beta(2)-GP1 positive than in beta(2)-GP1 negative sera. However, preadsorption of beta(2)-GP1 positive sera on beta(2)-GP1 coated ELISA plates reduced reactivity to oxidised cardiolipin by 80%, without affecting that to HSA-APP or HSA-MDA. CONCLUSIONS: Ethanol induced oxidative injury is associated with the development of antibodies targeting complexes between oxidised cardiolipin and beta(2)-GP1. These antibodies might account for high aPL titres observed in patients with severe ALD.

Adult↗