Abstract
BackgroundOxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. In this study, we examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity.ResultsHuman coronary artery endothelial cells (HCAECs) were treated with oxLDL in the presence or absence of antibody against MDA (anti-MDA) or apoB100 (anti-apoB100). In HCAECs treated with oxLDL (100 μg/ml) alone, DNA synthesis, cell viability, and expression of prosurvival fibroblast growth factor 2 (FGF2) were significantly reduced (P < 0.01 vs phosphate buffered saline–treated cells). These inhibitory effects of oxLDL were significantly attenuated in HCAECs cotreated with anti-MDA (0.15 μg/ml; P < 0.05 vs oxLDL-treated cells), but not in those cotreated with anti-apoB100. When we tested the effects of a panel of signal transduction modifiers on the signal transduction pathways of MDA in oxLDL-treated HCAECs, we found that MDA-induced cytotoxicity was mediated partly through the Akt pathway. Using a reporter gene assay, we identified an oxLDL-response element in the FGF2 promoter that was responsible for the transcriptional repression of FGF2 by oxLDL. The results of bisulfite genomic DNA sequencing showed that in HCAECs treated with oxLDL, the GC-rich promoter of FGF2 was heavily methylated at cytosine residues, whereas cotreatment with anti-MDA markedly reduced oxLDL-induced FGF2 promoter methylation.ConclusionOxLDL disrupts the growth and survival of HCAECs through an MDA-dependent pathway involving methylation of the FGF2 promoter and repression of FGF2 transcription. This novel epigenetic mechanism of oxLDL may underlie its atherogenicity in patients with atherosclerotic cardiovascular disease.
Highlights
Oxidized LDL is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood
After Human coronary artery endothelial cell (HCAEC) were treated with Oxidized LDL (oxLDL) (100 μg/ml) for 24 hours, DNA synthesis was decreased by 40% to 50% (Figure 1), a finding similar to those reported previously [11,12]
The inhibitory effect of oxLDL on DNA synthesis was markedly attenuated in HCAECs cotreated with 0.15 μg/ml antiMDA, but not in those cotreated with anti-apoB100 (Figure 1)
Summary
Oxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. We examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity. Clinical data have indicated that MDA-type epitopes are prominent and prevalent and are important in cardiovascular disease; these antigens are key candidates for use in characterizing immune responses that are relevant to atherosclerosis [6,7]. We have previously shown that the endothelial damage caused by oxLDL is accompanied by the selective downregulation of fibroblast growth factor 2 (FGF2) and can be prevented by supplementing cells with exogenous FGF2 [11,12]. The downregulation of FGF2 expression, has become a recognized mechanism of endothelial dysfunction
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