Perturbation of Homocysteine Homeostasis Leads to Cellular Epigenetic Modification And Endothelial Injury in Acute Myocardial Infarction

Abstract

Homocysteine is a highly reactive, sulfur‐containing amino acid formed as a byproduct of the metabolism of the essential amino acid methionine. Homocysteine used to be thought of as a risk factor for atherosclerosis, but emerging data have suggested that S‐adenosylhomocysteine (SAH), an intermediate metabolite of homocysteine, might be a better indicator of vascular diseases. In this study, we investigated the epigenetic role and clinical significance of SAH‐homocysteine homeostasis in acute myocardial infarction. A cell culture system was established to assess the interplay between SAH and homocysteine using human coronary artery endothelial cells (ECs). Homocysteine alone did not affect EC survival up to 500 uM; however, in the presence of adenosine/EHNA, homocysteine (25–500 uM) dose‐dependently increased intracellular SAH and promoted TUNEL‐positive apoptotic cell death. There was a concomitant downregulation of fibroblast growth factor 2 (FGF2), a critical cytokine for EC survival, through extensive DNA methylation at CpG dinucleotides in the FGF2 gene promoter. These pro‐apoptotic effects in ECs were markedly attenuated when adenosine/EHNA was removed from the culture medium. In patients with acute ST‐elevation myocardial infarction (STEMI), the plasma SAH levels quantitated by liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS) were significantly higher than those in healthy controls. In contrast, the plasma homocysteine concentrations were similar between STEMI and healthy subjects. Moreover, STEMI patients who had an obvious clinical improvement also demonstrated a significant decrease in their plasma SAH levels at subsequent follow‐up. Our data conclude that the perturbation of SAH‐homocysteine homeostasis in ECs leads to cellular epigenetic modification and endothelial injury in acute myocardial infarction. Elevation of plasma SAH but not homocysteine in STEMI patients further supports the notion that SAH is a better indicator of vascular diseases than homocysteine.Support or Funding InformationThis work was supported by grants NSC101‐2320‐B‐002‐026 from the National Science Council and MOST‐106‐2314‐B‐002 ‐156 ‐MY2 (Dr. Po‐Yuan Chang) from the Ministry of Science and Technology, Taipei, Taiwan.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.