Journal
CARDIOVASCULAR RESEARCH
Volume 99, Issue 1, Pages 137-145Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvt062
Keywords
Aspirin; DNA methylation; Genes; Lipoproteins; Myocardial infarction
Categories
Funding
- National Science Council, Taipei, Taiwan [NSC 91-2320-B-002-185, 93-2314-B-002-125, 94-2320-B-002-121, 95-2320-B-002-116, 98-2628-B-002-088, 97-2320-B-002-057-MY3, NSC 100-2314-B-039-040-MY3]
- National Taiwan University Hospital, Taipei, Taiwan [NTUH 92A14, 93A02, 95S342]
- Taiwan Department of Health Clinical Trial and Research Center of Excellence [DOH102-TD-B-111-004]
- American Diabetes Association [1-04-RA-13]
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L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. Plasma L5 levels were compared between patients with STEMI (n 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (1.0 mM) accentuated the effects of L5. Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.
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