Abstract
BackgroundAntibodies against cardiolipin (aCL) are associated with increased risk of cardiovascular disease (CVD). We here determine the role of antibodies against oxidized CL (aOxCL).MethodsOne third of sixty-year olds from the Stockholm County were screened (2039 men, 2193 women), where 211 incident CVD-cases and 633 age- and sex-matched controls were identified (5–7 year follow-up). Antibodies were determined by ELISA and uptake of oxLDL in macrophages by FACScan.ResultsIgM aOxCL was lower among CVD cases than controls (p=0.024). aOxCL-levels were divided in quartiles with the highest quartile set as the reference group. After adjustment for smoking, BMI, type II diabetes, hypercholesterolaemia and hypertension, an increased risk was determined in the lowest quartile of IgM aOxCL (OR: 1.80, CI: 1.12–2.91, p=0.0159); OR for men in the lowest quartile was 2.46 (CI 1.34–4.53, p=0.0037) for CVD and for stroke: 12.28 (CI: 1.48-101.77, p=0.02). IgG aOxCL levels did not differ between quartiles in CVD-risk. High levels of IgM aOxCL (reaching significance above 86th) and IgG aOxCL (above 95th percentile) were associated with decreased risk of CVD (OR: 0.485, CI: 0.283-0.829; p=0.0082 and OR: 0.23, CI: 0.07-0.69; p=0.0091). aCL were not associated with CVD. oxCL but not CL competed out uptake of OxLDL in macrophages, and aOxLDL recognized oxCL but not CL. In contrast to aCL, aOxCL was not dependent on co-factor Beta2-glycoprotein-I.ConclusionsaOxCL is a novel risk/protection marker for CVD, with therapeutic implications. OxCL competes with oxLDL for uptake in macrophages and the possibility that aOxCL inhibits such uptake by interfering with same or similar epitopes in oxCL and oxLDL should be further studied.
Highlights
Antibodies against cardiolipin are associated with increased risk of cardiovascular disease (CVD)
We have recently reported that natural antibodies against phosphorylcholine of IgM subclass could be of interest, since low levels of these antibodies in several studies were associated with increased risk of CVD [4,5,6,7,8]
Preincubation with oxidized CL (OxCL) could inhibit up to 60-70% of IgM anti-OxCL binding to OxCL while CL (exposed to air over night had low capacity to influence anti-OxCL binding (Figure 2a)
Summary
Antibodies against cardiolipin (aCL) are associated with increased risk of cardiovascular disease (CVD). We here determine the role of antibodies against oxidized CL (aOxCL). Atherosclerosis is the major underlying cause of cardiovascular disease (CVD) as stroke and myocardial infarction (MI) and can be regarded as an inflammatory disease, where activated immune competent cells producing cytokines are typical features [1]. CL is found primarily in the inner mitochondrial membrane of euraryotic cells and in bacteria [9] which is interesting to note since mitochondria are believed to have a bacterial origin from an evolutionary point of view [10]. CL plays a central role in mitochondrial bioenergetics and appears to be of major importance in apoptosis and membrane dynamics [9]
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