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PubMed2001

Plasma cardiolipin in postmenopausal women in mauritius.

Data concerning the relationship between anti-cardiolipin antibodies and several diseases including myocardial infarction are not readily available for Mauritius. Anticardiolipin antibodies were measured using commercially available ELISA kits. Haematological profiles were measured using a Coulter Counter in the study population. Our study revealed significantly higher IgG and IgA levels as well as a strong correlation between decreased platelet levels and increased anticardiolipin status in the women during postmenopause. It is concluded that abnormal cardiolipin level could be an important risk factor for cardiovascular accidents among postmenopausal women in Mauritius.

Analysis of Variance↗

PubMed1992

[Cardiolipin antibodies in patients with myocardial infarction and unstable angina pectoris].

The clinical value of IgG and IgM cardiolipin antibodies (CLa) was examined in 22 patients with myocardial infarction and 9 patients with unstable angina (UA). Higher IgG levels were observed in 41% of MI patients and 55% of UA patients. There was a significant correlation between the detection of IgG CLa in patients with a history of myocardial infarction and the presence of left ventricular intracavitary thrombosis. The levels of IgG CLa were increased in 78% of patients with history of MI and in 32% without MI history. In addition, those of IgG CLa was higher in 80% of IM patients with signs of intracavitary thrombosis and in 38% with cavitary thrombosis. The findings suggest that antibodies to cardiolipin (of IgG in particular) make contribution to the development of thrombotic events in patients with coronary atherosclerosis in the absence of autoimmune pathology.

Adult↗

PubMed1992

[The clinico-immunological characteristics of central nervous system involvement in systemic lupus erythematosus: the relationship with antibodies to cardiolipin].

As many as 30 patients suffering from systemic lupus erythematosus (SLE) with the clinical signs of central nervous system derangement were examined. The mean age of the patients was 31.1 years. Using EIA, antibodies against cardiolipin (a-CL) were detected in 21 patients (70%). A-CL were revealed in all the patients with cerebral circulation impairment (CCI), choreic hyperkinesis, and convulsive syndrome. A-CL were discovered in 12 out of 18 SLE patients suffering from migraine-like headaches and in 4 out of 5 patients with mental disorders. Antibodies reacting with cardiolipin were mostly represented by the IgM isotype (80%) whereas a-CL-IgG were only identified in 13% of the patients, being associated in all the cases with a-CL-IgM. The high level of a-CL-IgG in blood serum was recorded in patients with the gravest patterns of nervous system derangement: CCI, occlusion of the retinal artery, psycho-organic and convulsive syndromes. All these patients demonstrated generalized reticular livedo. The high levels of a-CL-IgM were observed in SLE patients with choreic hyperkinesis and migraine-like headaches. Thus, the studies made it possible to trace the relationship between the development of certain neurological disorders (CCI, chorea, convulsive syndrome) in SLE patients and a-CL.

Adolescent↗

PubMed1994

[Clinical significance of anti-cardiolipin antibody in patients with systemic lupus erythematosus (SLE)].

Anti-cardiolipin antibody (aCL) in SLE patients reacts with cardiolipin/beta 2-GP1 complex. In order to disclose clinical significance of aCL in patients with SLE, aCL was determined by newly-developed anti-CL.beta 2-GP1 kit [Yamasa] EIA in 58 patients with SLE and the relationship between clinical manifestation of SLE and the presence of aCL was examined. Anti-cardiolipin antibody was positive in 20 patients (34.5%). In 20 SLE patients with positive aCL, livedo reticularis in 7, retinal vein thrombosis in 3, thrombophlebitis in 3 and other vasculo-occlusive episodes were observed as a characteristic clinical features of positive aCL. In contrast, a SLE patient complicated by ileal perforation due to necrotizing angiitis had negative aCL. Other clinical and laboratory features associated with aCL include recurrent fetal loss and thrombocytopenia.

Adolescent↗

PubMed1995

Analysis of variable region genes encoding anti-Sm and anti-cardiolipin antibodies from a systemic lupus erythematosus patient.

We have analysed the heavy and light chain variable region genes of two monoclonal antibodies, specific for the Sm antigen (RSP1; IgG kappa) and for cardiolipin (RSP4; IgM lambda), derived from a patient with active systemic lupus erythematosus (SLE). We have established that the variable region genes of the RSP1 autoantibody are somatic mutants of two germ line genes from the VH4 and V kappa 1 gene families. RSP4 antibody uses gene segments closely related to a VH3 gene member and to a V lambda 1 gene. The presence and distribution of the somatic mutations on both monoclonal autoantibodies are compatible with an antigen-driven immune process. These data suggest that in SLE a common antigenic stimulus may govern the autoantibody response against a wide spectrum of unrelated antigens, including native DNA, cardiolipin or Sm antigens, and provide further evidence that disease-associated autoantibodies are generated through antigen-selected somatic mutations.

Adult↗

PubMed1993

Measuring of cardiolipin antibodies and plasma lipids in different stages of coronary disease.

The study shows that antibodies to cardiolipin which are commonly found in young postinfarction cases may present a high risk for recurrent coronary manifestations. IgG and IgM antibodies to cardiolipin (C1Ab) were determined in 50 healthy individuals and 72 patients with coronary disease: 26 with acute infarction (A) and 24 with chronic infarction (C) as well as 22 with angina pectoris (AP). Lipid status parameters as risk factors were measured in all patients: total cholesterol, LDL, HDL cholesterol, triglycerides and apolipoprotein (a). Out of 72 patients suffering from coronary disease 20 (27.7%) had elevated C1Ab IgG (12.36 +/- 3.7 GPLU/ml). Rise of C1Ab IgM was not evidenced in any of the patients. C1Ab IgG were significantly elevated (p < 0.01) in patients with chronic myocardial infarction and angina pectoris (p < 0.05) while in cases of acute myocardial infarction significant elevation of these antibodies was not evidenced.

Angina Pectoris↗

PubMed1996

Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity.

beta2-Glycoprotein I (beta2GPI) is a phospholipid-binding serum protein with anticoagulant properties. It plays a vital role in the binding of anti-cardiolipin Abs purified from patients with autoimmune disease when assayed in a cardiolipin (CL) ELISA. Based on a three-dimensional model of beta2GPI, electrostatic calculations, and earlier peptide studies, a highly positively charged amino acid sequence, Lys282-Asn-Lys-Glu-Lys-Lys287, located in the fifth domain of beta2GPI, has been predicted to be the phospholipid binding site. We tested this hypothesis by site-directed mutagenesis of residues in the predicted phospholipid binding site and by assessing the mutants for phospholipid binding and anti-beta2GPI activity. A single amino acid change from Lys286 to Glu significantly decreased the binding of beta2GPI to CL. Double and triple mutants 2k (from Lys286, 287 to Glu286, 287), 2ka (from Lys284, 287 to Glu284, 287), and 3k (from Lys284, 286, 287 to Glu284, 286, 287) possessed no binding of Ab to beta2GPI in a CL ELISA, as well as no inhibitory activity on the binding of iodinated native beta2GPI to CL. These results indicate that the residues Lys284, Lys286, and Lys287 in the fifth domain of beta2GPI are critical for its binding to anionic phospholipids and its subsequent capture for binding of anti-beta2GPI Abs.

Amino Acid Sequence↗

PubMed2000

Two-dimensional electrophoresis and mass spectrometry identification of proteins bound by a murine monoclonal anti-cardiolipin antibody: a powerful technique to characterize the cross-reactivity of a single autoantibody.

Antigenic cross-reactivity, i.e., the capacity of a single antibody to react with apparently dissimilar structures, is a common characteristic of autoantibodies produced during systemic lupus erythematosus (SLE), an autoimmune disease developed by humans and certain strains of mice. Characterization of the extent of cross-reactivity of SLE-related autoantibodies may help identify the immunogenic stimulus, or stimuli, of autoantibody-secreting B-lymphocytes. Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was combined with mass spectrometry (MS) to identify cell proteins recognized by a single monoclonal autoantibody (mAb 4B7), derived from an (NZW x BXSB)F1 mouse and selected based on its capacity to react with cardiolipin, that binds to elements in the cytoplasm and nucleoli of HEp-2 cells as assessed by indirect immunofluorescence assay. Proteins from HL-60 extract were separated by 1-D and 2-D PAGE. Western blotting with mAb 4B7 after SDS-PAGE revealed four bands, two intensely labeled at 35 and 32 kDa, and two weaker ones at 20 and 60 kDa; three spots were detected after 2-D PAGE. After trypsin in-gel digestion of the three protein spots, MS yielded representative matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) Reflector or quadrupole-time of flight (Q-TOF) spectra. The three corresponding proteins were identified as the nucleolar phosphoprotein B23 (nucleophosmin), heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) and the 60 kDa Ro/SS-A RNP. Thus, these results showed that 2-D PAGE combined with MS constitutes a sensitive and powerful technique to characterize the full extent of cross-reactivity of a single mAb and may constitute a new approach to further characterize the immunogenic cellular components involved in the breakage of B-cell tolerance observed in SLE.

Amino Acid Sequence↗

PubMed2003

Age-related changes of the endogenous cardiolipin and plasmalogens of guinea pig kidney and their in vitro hydrolysis by endogenous phospholipases: a thin layer chromatographic analysis in conjunction with densitometric measurement.

The phosphoglycerides profile of guinea pig kidney, fetal, young adult, and aged, and their in vitro response to the endogenous lipolytic enzymes, mainly in the phospholipase group were determined by TLC technology in conjunction with densitometric measurement. Changes in phosphoglycerides profile subsequent to in vitro incubation of these tissues at pH 7.4, and 38 degrees C for 45 min and prior to phospholipid extraction has provided evidence relating to their respective lipolytic enzymes capabilities and age. These changes are mainly related to endogenous cardiolipin (CL), alkenyl phospholipids (phosphatidyl ethanolamine and phosphatidyl choline) and their endogenous deacylation to their respective lyso derivatives monolysocardiolipin (MLCL), lyso alkenyl phosphatidyl ethanolamine (LPE), and lyso alkenyl phosphatidyl choline (LPC) by endogenous phospholipases. The hydrolysis of the plasmalogen confirms the action of endogenous PLA(2) on sn-2 fatty acids of these compounds.

Aging↗

PubMed1996

Monoepoxide production from linoleic acid by cytochrome c in the presence of cardiolipin.

We found that cytochrome c (Cyt c) could oxidize cardiolipin (CL), and detected monoepoxides of linoleic acid (LA) in the fatty acids constituting the oxidized CL. We also found that in the presence of CL and Cyt c, free LA was oxidized and LA monoepoxides were produced. The aim of this study was to elucidate the mechanism of this lipid peroxidation. We concluded that ferric Cyt c produced some radical species from water-soluble oxygen in the presence of CL (CL-Cyt c system) and that radicals oxidized free LA or CL. The CL-Cyt c system may be another LA monoepoxide producing system in the neutrophil and may account for the lipid peroxidation observed in the ischemia-reperfusion-induced cardiac injury.

Cardiolipins↗

PubMed1999

Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation.

To explore the molecular mechanism underlying the translocation of cytochrome c from the mitochondrial inner membrane to the cytosol during apoptosis, we analyzed the molecular interaction between cytochrome c and cardiolipin (CL) by (1)H NMR spectroscopy. Bovine heart CL induced a drastic broadening of the linewidth of the downfield signals at 31.4 and 34.2 ppm assigned to the heme methyl group-3 and -8, respectively, of horse heart cytochrome c. In contrast, CL mono- and dihydroperoxides were less active in broadening the signals than CL, and CL trihydroperoxides induced almost no broadening of their linewidth. This finding suggests that the peroxidation of CL induces a release of cytochrome c from mitochondria into the cytosol, which release induces apoptosis in the cells.

Animals↗

PubMed1985

Multiple venous and arterial thromboses associated with the lupus anticoagulant and antibodies to cardiolipin in the absence of SLE.

A 53-year-old man with a history of multiple venous thromboses presented with widespread occlusions of the abdominal arterial system associated with the presence of the "lupus anticoagulant" and antibodies to cardiolipin in serum. There was no serological evidence of systemic lupus erythematosus and vasculitis of the affected vessels was not evident on post mortem examination. The presence of these antibodies, associated with a tendency to thrombosis, positive anti nuclear factor and cryoglobulinaemia were the only indicators of an "auto-immune" disturbance in this patient.

Abdomen↗

PubMed1989

Cardiolipin-fluorescent (M1) antimitochondrial antibody and cholestatic hepatitis in secondary syphilis.

A 27-year-old black male with secondary syphilis and cholestatic jaundice is presented. The liver biopsy was believed to be most consistent with large bile duct obstruction, but both the ultrasound and endoscopic retrograde cholangiography were normal. Prior to treatment with penicillin, his serum was positive for antimitochondrial antibody. After treatment, the antibody was no longer detectable and the jaundice gradually resolved. The patient's pretreatment serum was, after further analysis, found to be positive for the antibody to the M1 antimitochondrial antigen subtype, which is identical to cardiolipin, the antigen in both the VDRL and Wasserman tests. A review of hepatic involvement in secondary syphilis is presented.

Adult↗

PubMed1996

Dietary fatty acid composition induces comparable changes in cardiolipin fatty acid profile of heart and brain mitochondria.

The fatty acid profile of cardiolipin (CL) from brain and cardiac mitochondria was measured to determine whether CL isolated from these two tissue sources responded similarly to alterations in dietary fat composition. Male Wistar rats were fed 20% (w/w) diets containing 2 to 12% (w/w) 18:2n-6 for four weeks. Despite higher baseline levels of CL 18:2n-6 in cardiac (54 +/- 1% of total fatty acids) compared to brain (13 +/- 1%) mitochondria, CL 18:2n-6 levels increased in proportion to dietary 18:2 levels. The degree of change in 18:2n-6 was comparable with both tissues showing an approximate 1.5- to 2-fold increase. The time course of changes in CL fatty acid profile was examined in a subsequent experiment in which animals were fed 20% (w/w) fat diets containing either 3 or 15% alpha-linoleate. Changes in cardiac CL 18:1, 18:2n-6, and 22:6n-3 levels were observed within one week of feeding. While statistically significant differences were not observed in brain CL until the second week of feeding, the time course did not differ substantively from that observed in heart. The results from this study suggest that while baseline fatty acid profile of cardiac and neural CL differ, mitochondria from both tissues show comparable sensitivity to changes in dietary fat composition. Furthermore, it would appear that the turnover rate of fatty acids in CL is similar in both tissues.

Animals↗

PubMed1992

Effects of various dietary fats on cardiolipin acyl composition during ontogeny of mice.

Cardiolipin (CL) is a unique mitochondrial phospholipid, containing up to 85 wt% 18:2n-6 in mammals. The influence of maternal dietary fatty acids on the acyl composition of offspring CL has not been examined previously. Adult female mice were thus fed diets rich in 18:1n-9 (olive oil), 18:2n-6 (safflower oil), 18:3n-3 (linseed oil) or 20:5n-3 and 22:6n-3 (fish oil/safflower, 9:1, w/w), for a five month period, encompassing two breeding cycles. Offspring from the second breeding cycle were then fed these diets. The acyl composition of CL, phosphatidylcholine and phosphatidylethanolamine from liver and heart was evaluated from mice killed 3, 18 and 42 days after parturition. The primary nutrient sources at these three time points were transplacental nutrients, breast milk and the diet, respectively. Maternal diet was found to influence the acyl composition of CL via both placental transfer of fatty acids and breast milk. Fish oil feeding resulted in replacement of a substantial portion of 18:2n-6 with 22:6n-3; after 42 days, the area% of 18:2n-6 in heart CL was reduced from 62% in safflower oil fed mice to 12%. In comparison to fish oil feeding, linseed oil feeding resulted in a much lower accumulation of 22:6n-3. Olive oil feeding resulted in substantial replacement of 18:2n-6 with 18:1n-9 (18:2n-6 was reduced from 62% to 31%). Physiologically, these findings are relevant because changes in CL acyl composition may influence the activity of associated inner mitochondrial membrane enzymes.

Aging↗

PubMed1993

pH-dissociation characteristics of cardiolipin and its 2'-deoxy analogue.

Cardiolipin (CL) is found in inner mitochondrial membranes and the plasma membrane of aerobic prokaryotes. CL is tightly bound to those transmembrane enzymes associated with oxidative phosphorylation. CL has earlier been reported to have a single pK at low pH. We have titrated CL in aqueous suspension (bilayers) and in solution in methanol/water (1:1, vol/vol) and found it to display two different pK values, pK1 at 2.8 and pK2 initially at 7.5 but shifting upwards to 9.5 as the titration proceeds. The unusually high pK2 might be explained by the formation of a unique hydrogen bond in which the free hydroxyl on the central glycerol forms a cyclic intramolecular hydrogen-bonded structure with one protonated phosphate (P-OH group). We have therefore chemically synthesized the 2'-deoxycardiolipin analogue, which lacks the central free hydroxyl group, and measured its pH-dissociation behavior by potentiometric titration, under the same conditions as those for CL. The absence of the hydroxyl group changes the titration dramatically so that the deoxy analogue displays two closely spaced low pK values (pK1 = 1.8; pK2 = 4.0). The anomalous titration behavior of the second dissociation constant of CL may be attributed to the participation of the central glycerol OH group in stabilizing the formation of a cyclic hydrogen-bonded monoprotonated form of CL, which may function as a reservoir of protons at relatively high pH. This function may have an important bearing on proton pumping in biological membranes.

Cardiolipins↗

PubMed2004

Binding and release of cytochrome c in brain mitochondria is influenced by membrane potential and hydrophobic interactions with cardiolipin.

Factors influencing the release and anchorage of cytochrome c to the inner membrane of brain mitochondria have been investigated. Metabolic activity of mitochondria caused a decrease in the membrane potential delta psi(m), accompanied by detachment of the protein from the inner membrane. In a model system of cytochrome c reconstituted in cardiolipin (CL) liposomes, phosphate was used to breach the hydrophilic lipid-protein interactions. About 44% cytochrome c was removable when heart CL (80% 18:2n-6) was employed, whereas the remaining protein accounted for the tightly bound conformation characterized by hydrophobic lipid-protein interactions. Cytochrome c release from brain CL liposomes was higher compared to heart CL, consistent with lower polyunsaturated fatty acid content. The release was even higher with CL extracted from metabolically stressed mitochondria, exhibiting more saturated fatty acid profile compared to control (30% vs. 17%). Therefore, weakening of the hydrophobic interactions due to saturation of CL may account for the observed cytochrome c release from mitochondria following metabolic stress. Moreover, mitochondria enriched with polyunsaturated CL exhibited higher delta psi(m), compared to less unsaturated species, suggesting that CL fatty acid composition influences delta psi(m). Mitochondria incorporated exogenous cytochrome c without protease-sensitive factors or delta psi(m). The internalized protein anchored to the inner membrane without producing swelling, as monitored by forward and side light scattering, but produced delta psi(m) consumption, suggesting recovery of respiratory activity. The delta psi(m) decrease is ascribed to a selected mitochondrial population containing the incorporated cytochrome c.

Animals↗

PubMed2002

Evidence of a tetradocosahexaenoic cardiolipin in some marine bivalves.

Separation of phospholipid classes in lipid extracts from the scallop Pecten maximus, the Pacific oyster Crassostrea gigas, and the blue mussel Mytilus edulis was conducted using HPLC. An isolated polar lipid fraction was found to contain a very high level of DHA, up to 80 mol% of the total FA. MS with electrospray ionization in the positive-ion mode, tandem MS (MS-MS) and multidimensional NMR spectroscopy were used to analyze the detailed chemical structure of this polar lipid fraction. The isolated fraction contained exclusively cardiolipin (CL) molecules, predominantly in a form with four docosahexaenoyl chains (Do4CL). To the best of our knowledge, this is the first time that such a CL form has been analytically characterized and described in these three bivalve species. This tetradocosahexaenoic CL is presumed to reflect a specific adaptation in bivalves that enhances the structural and functional mechanisms of biomembranes in response to variations in environmental conditions (temperature, salinity, emersion).

Animals↗