ABSTRACT
Immune complexes (IC) containing predominantly malondialdehyde-LDL and the corresponding autoantibodies (MDA-LDL IC) predict acute cardiovascular events, while IC rich in oxidized LDL (oxLDL IC) predict cardiovascular disease progression. Our objective was to determine mechanisms that could explain these prognostic differences. We compared the effects of the interaction of oxLDL, MDA-LDL and the corresponding IC with human macrophages focusing on apoptosis, metalloproteinases, and proinflammatory cytokines. MDA-LDL IC induced higher degrees of apoptosis, higher levels of caspase-3 expression, and increased expression and release of MMP-1 and TNF compared to MDA-LDL, oxLDL, and oxLDL IC. The pro-apoptotic effects of MDA-LDL IC were inhibited by blocking TNFR 1 or FcγRI. Blocking FcγRI abrogated the induction and expression of MMPs and proinflammatory cytokines by MDA-LDL IC. In conclusion, the interaction of MDA-LDL IC with FcγRI triggers macrophage apoptosis and increased expression and release of TNF and MMP-1, which can lead to the rupture of unstable plaques.
Subject(s)
Antigen-Antibody Complex/immunology , Apoptosis/immunology , Atherosclerosis/immunology , Autoantibodies/immunology , Lipoproteins, LDL/immunology , Macrophages/immunology , Malondialdehyde/analogs & derivatives , Plaque, Atherosclerotic/immunology , Antigen-Antibody Complex/metabolism , Atherosclerosis/metabolism , Autoantibodies/metabolism , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Caspase 3/metabolism , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Cytokines/immunology , Disease Progression , Gene Expression , Humans , Interleukin-6/genetics , Interleukin-6/immunology , Lipoproteins, LDL/metabolism , Macrophages/metabolism , Malondialdehyde/immunology , Malondialdehyde/metabolism , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 9/genetics , Plaque, Atherosclerotic/metabolism , Receptors, IgG/antagonists & inhibitors , Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors , Tissue Inhibitor of Metalloproteinase-1/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
AIMS: This study was undertaken to determine whether levels of inflammation and endothelial dysfunction biomarkers in serum samples collected at baseline in the Diabetes Control and Complications Trial (DCCT) cohort could predict the development of retinopathy. METHODS: Levels of clotting/fibrinolysis, inflammation and endothelial dysfunction biomarkers were measured in 1391 subjects with type 1 diabetes to determine whether their levels predicted increased risk to develop or accelerate progression of retinopathy during 16years of follow-up. RESULTS: Using regression models adjusted for DCCT treatment group, duration of diabetes, baseline retinopathy scores, HbA1c and albumin excretion rate, the baseline levels of sE-selectin and PAI-1 (active) were significantly associated with increased risk of a 3-step progression in retinopathy score in the primary prevention cohort (PPC). After adjusting for additional covariates (e.g., ACE/ARB and statin therapy), this association persisted. Levels of active and total PAI-1 in the same group were also significantly associated, after similar adjustments, with the time to progress to severe non-proliferative retinopathy during the follow-up period (54 and 29%, respectively of increased risk). No associations were observed in the secondary intervention cohort for any of the outcomes. CONCLUSIONS: High levels of sE-selectin and PAI-1 are associated with the development of retinopathy in patients with uncomplicated type 1 diabetes.
