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PubMed1994

A cardiolipin-activated protein kinase from rat liver structurally distinct from the protein kinases C.

A cardiolipin- and protease-activated protein kinase (PAK) has been isolated from cytoplasmic extracts of rat liver. The enzyme (PAK-1) phosphorylates the ribosomal protein S6-(229-239) peptide analogue and can be activated by limited proteolysis. Partial amino acid sequences of tryptic peptides derived from both the purified 116-kDa PAK-1 holoenzyme and its active catalytic fragment reveal that the catalytic domain is most related (50-58% identity) to the protein kinase C family. PAK-1 has protein and peptide substrate specificities distinct from those of known protein kinase C isoforms and is insensitive to inhibition by the protein kinase C-alpha-(19-31) pseudosubstrate peptide. Phosphatidylserine, diacylglycerol, and phorbol ester do not activate PAK-1 toward the S6 peptide substrate. However, other acidic phospholipids, the most effective being cardiolipin, activate PAK-1 to a similar extent as trypsin. The PAK-1 catalytic activities generated through activation by cardiolipin or limited proteolysis were kinetically similar, with Km values of 3.6 and 3.4 microM, respectively, for the S6-(229-239) peptide substrate. However, differences were observed in the catalytic activities with protamine sulfate and the glycogen synthase-(1-12) peptide analogue as substrates. It was concluded that PAK-1 is a phospholipid-regulated protein kinase with a primary structure, substrate specificity, and mechanism of regulation in vitro distinct from those of any known member of the protein kinase C superfamily.

Amino Acid Sequence↗

PubMed1993

Amino acid sequence of the region of beta 2-glycoprotein 1 (gp1) which mediates binding of autoantibodies to the cardiolipin-gp1 complex in humans.

Anticardiolipin antibodies (ACA) in sera from patients with autoimmune and infectious diseases were tested for binding to beta 2-glycoprotein 1 (gp1) in order to determine whether human gp1 acts as a cofactor for the binding of ACA to cardiolipin (CL) or as an antigen recognized by ACA. While none of the ACA-positive sera tested recognized gp1 by itself, gp1 was necessary for the binding of ACA to CL in sera from four patients with autoimmune diseases. In three of the four sera the presence of lupus anticoagulant (LA) was detected by prolonged partial thromboplastin time (PTT). Examinations using the bovine equivalent of human gp1 contained in fetal calf serum (FCS) and adult bovine serum (ABS) showed that the human protein can be replaced by the bovine equivalent in the enzyme-linked immunosorbent assay (ELISA). Using affinity-purified antibodies directed against the CL-gp1 complex it was shown that the binding of these antibodies is dependent on the concentration of the bovine gp1 equivalent contained in the formed complex. Similar results found with the human gp1 confirmed this assertion. In order to find out which region of gp1 might mediate the binding between ACA and cardiolipin, we examined to what extent selected oligopeptide sequences of gp1 can substitute for the protein. Peptide P2 (representing the amino acids at positions 268-278 of the gp1 molecule) and gp1 showed about the same binding capacity. Histidine in this peptide seems to be essential for the binding to CL as we found decreased binding with peptides modified in this position. Conclusions from this work show that gp1 does not act as a relevant antigen for ACA, but occupies an essential function in the complex formed with cardiolipin for a certain group of ACA.

Amino Acid Sequence↗

PubMed1998

Monoclonal anti-cardiolipin antibodies from New Zealand Black x New Zealand White F1 mice react to thrombomodulin.

The reactivity with and affinity for thrombomodulin (TM) of monoclonal anti-cardiolipin Abs (MoaCL), derived from a New Zealand Black x New Zealand White F1 (NZB/W F1) mouse, were studied to investigate the pathogenicity of anti-cardiolipin Abs (aCL). Four of eighteen MoaCL were found to react with rabbit TM when examined using ELISA. These four MoaCL also reacted with synthetic peptide that included the epidermal growth factor-like domain of human TM, a binding site for thrombin. The reaction with TM of these four MoaCL was inhibited by bovine thrombin. When the affinity for TM of the MoaCL was determined, the dissociation constants (Kd) ranged from 4.8 x 10(-9) to 4.7 x 10(-8) M. By contrast, examination of the affinity for cardiolipin (CL) gave values from 8.3 x 10(-6) to 7.4 x 10(-5) M. Thus, these MoaCL reacted to TM with a higher affinity than to CL. Moreover, these MoaCL also bound to TM on HUVEC and down-regulated the expression level of TM on the surface of HUVEC due to internalization of TM. The binding of thrombin to TM is known to initiate rapid protein C activation, and complexes of activated protein C and protein S show anticoagulatory activity. Thus, the present studies suggest that certain pathogenic aCL cross-react with TM and induce down-regulation of TM on endothelial cells, followed by induction of thrombosis.

Animals↗

PubMed1994

Establishment of two distinct anti-cardiolipin antibody-producing cell lines from the same individual by Epstein-Barr virus transformation.

Two anti-cardiolipin antibody (ACA)-producing cell lines were established, using Epstein-Barr virus transformation followed by a repeated cluster-picking from the same individual with antiphospholipid syndrome who had a history of 8 consecutive fetal losses and deep venous thrombosis. Characterization of the two ACAs derived from these cell lines revealed that one (Ab-019, subclass IgM, kappa) reacted exclusively with cardiolipin and showed strong lupus anticoagulant activity, while the other (Ab-226, subclass IgM, lambda) reacted with negatively charged phospholipids such as phosphatidylserine and phosphatidylglycerol, as well as cardiolipin. Furthermore, Ab-226 showed reactivity with human umbilical vein endothelial cells whereas Ab-019 did not. It is suggested that ACA is heterogeneous even in the same individual, and that reactivity against negatively charged phospholipids corresponds to reactivity against endothelial cell.

Adult↗

PubMedDate not supplied

The neuroimaging features of the cardiolipin antibody syndrome.

The purpose of our study was to define the neuroimaging features of the cardiolipin antibody syndrome. Thirty-eight patients with elevated anticardiolipin antibody titers were studied with magnetic resonance imaging or computed tomography or both. Two patients underwent cerebral angiography. All patients had recurrent transient ischemic attacks, amaurosis, or strokes. One patient had normal imaging findings. The remaining patients had a combination of infarction and atrophy. Focal infarcts, the most common finding, were seen in 32 patients. Cerebral atrophy was seen in 26 patients and was the only radiographic finding in 5. Angiography demonstrated dramatic abnormalities in the distal portions of the anterior and posterior circulations, with multiple stenosis and occlusions and extensive pial and transdural collateral networks. The cardiolipin antibody syndrome should be suspected in young patients with transient ischemic attacks or strokes in the absence of the usual risk factors for cerebrovascular disease. The presence of raised anticardiolipin antibody titers or the cardiolipin antibody syndrome in patients with lupus, in those with other connective tissue diseases, and in patients without overt manifestations of an autoimmune disorder should be viewed as a risk factor for future ischemic cerebrovascular events. Further understanding of the precise role of these antibodies in the pathogenesis of vascular thrombosis may lead to a better understanding of the mechanisms underlying certain forms of stroke.

Adolescent↗

PubMed1995

Antibodies to oxidized low-density lipoprotein and to cardiolipin in nonpregnant and pregnant women with habitual abortion.

OBJECTIVE: To determine the occurrence of antibodies to oxidized low-density lipoprotein (LDL) in women with a history of habitual abortion before and during pregnancy. DESIGN: Immunoglobulin G class antibodies to malondialdehyde modified LDL were determined by a solid-phase ELISA in 42 habitual aborters before pregnancy, in 39 patients during pregnancy, and in 23 comparable nonpregnant and 22 pregnant control women without a history of abortion. In addition, we assessed the presence of anticardiolipin antibodies by ELISA in the same sera. SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. RESULTS: Early pregnancy was accompanied by a decrease in the median levels of antibodies to oxidized LDL both in habitual aborters and in the control series. Only one patient exhibited a raised level of antibodies to oxidized LDL before pregnancy but, during pregnancy, nine patients (23%) had elevated levels of antibodies to oxidized LDL, similar to women with a favorable outcome of pregnancy (6/27, 22%) and in women whose current pregnancy also ended in abortion (3/12, 25%). Cardiolipin binding antibodies were detected in three habitual aborters before pregnancy (7%) and in nine women during pregnancy (23%), with a tendency to be more frequent in patients with miscarrying pregnancies than in those with continuing pregnancies (4/12, 33% and 5/27, 19%). Antibodies to oxidized LDL and cardiolipin were simultaneously present in three habitual aborters with continuing pregnancies. CONCLUSIONS: Increased levels of antibodies to oxidized LDL and cardiolipin may be associated with habitual abortion.

Abortion, Habitual↗

PubMed1993

Anaesthetic implications of the anti-cardiolipin antibody syndrome.

The anti-cardiolipin antibody syndrome (or anti-phospholipid antibody syndrome) is characterized by the presence of autoantibodies to phospholipids. Its major association is with systemic lupus erythematosus. It is characterized further by in vitro prolongation of phospholipid-dependent coagulation tests. However, in vivo it is associated with a markedly increased incidence of thrombosis, both arterial and venous. We describe the case of a 36-yr-old female patient with the anti-cardiolipin antibody syndrome who presented initially for diagnostic laparoscopy and later for exploratory laparotomy. Her postoperative course after the first general anaesthetic was complicated by disseminated intravascular coagulation and adult respiratory distress syndrome. After the second operation, she deteriorated further with worsening cardiac, renal and respiratory function and eventually died. As far as we are aware, this is the first reported case of the anti-cardiolipin antibody syndrome in anaesthetic literature. Further aspects of this puzzling condition and its anaesthetic implications are discussed.

Adult↗

PubMed1995

Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease.

OBJECTIVES: To investigate the prevalence of anticardiolipin and antiendothelial cell antibodies in patients operated on for atherosclerotic peripheral vascular disease before 50 years of age. The hypothesis to be tested was whether antibodies associated with an immune/inflammatory damage to the vascular wall were associated also with early atherosclerosis. DESIGN: A case-control study. SETTING: Departments of surgery and an immunological research laboratory, and routine laboratories of two tertiary referral hospitals. SUBJECTS: All patients operated for atherosclerotic peripheral vascular disease before 50 years of age. Sixty-two patients (33 males, 29 females), and 67 age- and sex-matched controls participated. The diagnosis of atherosclerosis was made on the basis of the clinical presentation and angiographic visualization of the diseased vasculature. MAIN OUTCOME MEASURES: Subjects were compared for the prevalence of anticardiolipin and antiendothelial cell antibodies, altered serum lipoprotein levels, smoking, diabetes, hypertension, and signs of inflammation. RESULTS: Antibodies against endothelial cells and cardiolipin were found in 12.9 and 14.5% of the patients, respectively, which was higher than observed in the control group (P < 0.05). Sixty per cent of patients with antibodies were females. Conventional risk factors were more often noted in the patient group. However, patients with antibodies against endothelial cell and/or cardiolipin had a lower prevalence of hyperlipidaemia/dyslipidaemia when compared to patients without these antibodies (P < 0.05). CONCLUSIONS: Antibodies against endothelial cells and cardiolipin are present in a subset of patients with clinical and angiographic diagnosis of severe premature atherosclerotic peripheral vascular disease. The lower occurrence of hyperlipidaemia/dyslipidaemia in patients with autoantibodies, in comparison to patients without the antibodies, suggests that these antibodies have a role in vascular damage.

Adult↗

PubMed1970

Cardiolipin-specific phospholipase D activity in Haemophilus parainfluenzae.

A highly active phospholipase D that is specific for cardiolipin was detected in the gram-negative bacterium Haemophilus parainfluenzae. Previously reported phospholipase D preparations have come exclusively from higher plants. The bacterial enzyme hydrolyzed cardiolipin to phosphatidyl glycerol and phosphatidic acid. During the incubation, phosphatidic acid disappeared. Phosphatidyl ethanolamine, methylated phosphatidyl ethanolamines, phosphatidyl choline, and phosphatidyl glycerol were not hydrolyzed when cardiolipin was rapidly hydrolyzed.

Autoradiography↗

PubMed1995

Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men.

BACKGROUND: Data concerning the relation between antiphospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort. METHODS AND RESULTS: The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non-high-density lipoprotein cholesterol, > or = 5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361; P < .005). Subjects with the antibody level in the highest quartile of distribution had a relative risk for myocardial infarction of 2.0 (95% confidence interval, 1.1 to 3.5) compared with the remainder of the population. This risk was independent of confounding factors, such as age, smoking, systolic blood pressure, low-density lipoprotein (LDL), and high-density lipoprotein. There was a correlation between the levels of aCL antibodies and antibodies to oxidized LDL (r = .40, P < .001), and their joint effect was additive for the risk. CONCLUSIONS: In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.

Antibodies, Anticardiolipin↗

PubMed1996

Antibodies against phospholipids other than cardiolipin: potential roles for both phospholipid and protein.

Autoantibodies to phospholipids other than cardiolipin have received less attention, to date, than anti-cardiolipin antibodies. This review focuses on these antibodies and potential roles for both phospholipid and protein in their reactivity. We review data in the literature indicating that antibodies to phosphatidylethanolamine and some lupus anticoagulant antibodies recognize phospholipid-binding proteins in association with phospholipid. Kininogens appear to be involved in the binding of antibodies to phosphatidylethanolamine, while phosphatidylserine-binding proteins, such as prothrombin and annexin V, have been implicated in lupus anticoagulant antibody recognition. These proteins bind to phospholipids that normally reside in the inner monolayer of the cell membrane, suggesting that exposure of these lipids is necessary for protein binding and antibody recognition to occur. In contrast, other autoantibodies, in particular those reactive with erythrocytes, appear to be directed at phospholipids that normally occur in the outer membrane leaflet, such as phosphatidylcholine. In summary, there is clearly accumulating evidence that antibodies to phospholipids other than cardiolipin recognize epitopes on phospholipid-binding proteins. It is not clear whether recognition of these epitopes is due to an increase in antigen density or a change in the protein or phospholipid structure, but it is likely that both protein and phospholipid structure play an important role in the in vivo interactions of these antibodies.

Annexin A5↗

PubMed1998

[Polymyalgia rheumatica and myelitis associated with anti-cardiolipin antibody].

A 78-year-old woman was admitted to our hospital on September 14, 1992, because of systemic myalgia and stiffness, joint pain, and gait disturbance. She had begun to feel headache and pain in the neck and shoulder in the middle of August, 1992. The pain became systemic, and was accompanied by a low-grade fever, which was unresponsive to NSAIDs. On admission, she had no joint swelling or deformities in the extremities. Neurological examination revealed weakness in the right leg, hypoalgesia below the left C4 level, hyperreflexia in the right extremities, and right Babinski's sign. The erythrocyte sedimentation rate was very high (100 mm/h). Levels of other acute phase reactants were also high. Tests for antinuclear antibody and anti-cardiolipin antibody were positive, but a test for rheumatoid factor was negative. Creatine kinase activity was within normal limits. A T1-weighted magnetic resonance image of the cervical spine at 0.5 T showed an intramedullary low signal. A T2-weighted image showed a borderless spindle-like high signal. Four nodules enhanced by Gd DTPA were seen at C1-C4. The age at onset, myalgia, stiffness, and erythrocyte sedimentation rate were considered to be consistent with a diagnosis of polymyalgia rheumatica. Glucocorticoid treatment was therefore started, and a dramatic clinical improvement was evident within a few days. The patient was discharged from hospital on November 30, 1992. To our knowledge, myelopathy complicated by polymyalgia rheumatica has never been reported previously. Recently, some patients with polymyalgia rheumatica have been reported to have anti-cardiolipin antibody in serum. In the present case anti-cardiolipin antibody may have played a role in the formation of microemboli or in angitis of the cervical spine.

Aged↗

PubMed1999

[Cardiolipin antibodies dependents on beta2-glycoprotein-1 in antiphospholipid syndrome].

AIM: To study beta2-GP-I-dependent binding of phospholipid antibodies (PAb) to phospholipids and this process participation in pathogenesis of antiphospholipid syndrome (APS). MATERIALS AND METHODS: IgG-fractions and sera from 20 patients with APS. Cofactor activity of beta2-GP-I isolated from serum of healthy donors was examined with modified immunoassay. RESULTS: Contrary to donor IgG, binding of IgG fractions isolated from sera of APS patients with cardiolipin grows dose-dependently in the presence of beta2-GP-I. Cofactor activity of beta2-GP-I is confirmed in the study of sera of APS patients. Sera containing beta2-GP-I-dependent antibodies to cardiolipin (aCL), unlike aCL-negative sera, react with solid-phase immobilized beta2-GP-I. CONCLUSION: It is confirmed that beta2-GP-I participates in interaction of PAb with cardiolipin. Pathogenetic implication of beta2-GP-I-dependent PAb for onset of APS is discussed.

Adult↗

PubMed1992

[Anti-cardiolipin antibodies in Horton's disease].

A prospective study on 11 patients with temporal artery biopsy-proven arteritis examined the frequency and significance of anti-cardiolipin antibodies. Antibody levels in 7 patients were higher than 20 units but were not correlated with an inflammatory syndrome, as assessed by measurement of 4 inflammatory proteins (fibrinogen, C-reactive protein, orosomucoid and haptoglobin). These 7 patients were treated with steroids and their antibody levels returned to the normal range after 4 to 16 weeks of therapy, later than the inflammatory proteins. Two patients had slight increases of their anti-cardiolipin antibody levels, but no signs of clinical relapse or increases of inflammatory proteins were observed. In this study, no correlation was found between the presence of anti-cardiolipin antibodies and the occurrence of ischemic complications in 6 of the 11 patients.

Aged↗

PubMed1970

Novel preparation of cardiolipin from beef heart.

A new method is described for the isolation of beef heart cardiolipin. A lipid-protein complex, rich in cardiolipin, is obtained by a one-step solvent fractionation of the tissue total lipid extract. Cardiolipin in the complex is largely freed of protein by salt denaturation and is further purified by gel filtration on Sephadex LH-20 followed by column chromatography on bicarbonate-treated silicic acid. The highly purified product is obtained as the sodium salt in a yield of 85-100 mg/100 g of fresh tissue.

Animals↗

PubMed2002

Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome.

Barth syndrome is an X-linked cardiac and skeletal mitochondrial myopathy. Barth syndrome may be due to lipid alterations because the product of the mutated gene is homologous to phospholipid acyltransferases. Here we document that a single mitochondrial phospholipid species, tetralinoleoyl-cardiolipin, was lacking in the skeletal muscle (n = 2), right ventricle (n = 2), left ventricle (n = 2), and platelets (n = 6) of 8 children with Barth syndrome. Tetralinoleoyl-cardiolipin is specifically enriched in normal skeletal muscle and the normal heart. These findings support the notion that Barth syndrome is caused by alterations of mitochondrial lipids.

Adolescent↗

PubMed1990

Cardiolipin liposomes: a novel flow reagent for detection of anticardiolipin antibodies.

The association of autoantibodies with specificity for phospholipids and an increased risk for thromboembolic phenomena has received considerable recent clinical attention. These autoantibodies have been reported in patients with defined autoimmune disorders as well as in patients with no other obvious autoimmune disease symptoms other than isolated or recurrent thromboembolic disease. A significant component of this autoimmune response appears to be related to cardiolipin-directed antibodies. Most studies reported to date have used either an enzyme immunoassay or a radioimmunoassay for detection and quantitation of antiphospholipid antibodies. We have developed a novel flow cytometric assay for detection of anticardiolipin antibodies. The assay, by analogy to polystyrene microsphere assay, utilizes cardiolipin liposomes as solid-phase microspheres for antigen presentation. In comparison to enzyme-linked immunosorbent assay, the flow assay shows similar sensitivity by serum titration, has immunoglobulin class specificity, and is semiquantitative as currently designed. The flow assay is relatively easy to perform and should allow detection of other antiphospholipid specificities with tailoring of the phospholipid makeup of the liposomes.

Autoantibodies↗

PubMed1993

5-aminolevulinic acid induces lipid peroxidation in cardiolipin-rich liposomes.

5-Aminolevulinic acid (ALA), a heme precursor accumulated in lead poisoning and acute intermittent porphyria, is known to undergo metal-catalyzed aerobic oxidation to yield reactive oxygen species. In phosphatidylcholine:cardiolipin (80:20) liposomes ALA (0.1-3.0 mM) promoted lipid peroxidation as evaluated by the formation of conjugated dienes and 2-thiobarbituric-reactive substances (TBARS). TBARS formation was dependent on ALA concentration and incubation time. ALA-induced lipid peroxidation was associated with an increase in liposome permeability as measured by the release of encapsulated carboxyfluorescein. alpha-Tocopherol (0.1-0.5 mol %), an efficient oxyradical scavenger, inhibits lipid peroxidation and prevents carboxyfluorescein release, suggesting that the permeabilization of liposomes is mainly due to lipid peroxidation. Cardiolipin, a major component of mitochondrial inner membrane, was particularly susceptible to ALA-induced lipid peroxidation. These results may be relevant to the previously observed Ca(2+)-dependent permeabilization of the inner membrane of rat liver mitochondria promoted by external 0.1-1.0 mM ALA; this mechanism has been implicated in the pathophysiology of acute intermittent porphyria and lead poisoning.

Aminolevulinic Acid↗