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CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells. | LitMetric

AI Article Synopsis

  • * In this study, researchers deleted the CRIF1 gene in human umbilical vein endothelial cells and mice, which resulted in increased homocysteine levels and decreased folate cycle intermediates like MTHF and THF.
  • * The enzyme dihydrofolate reductase (DHFR) was found to be less active and lower in expression due to CRIF1 deletion, while boosting DHFR levels in these cells reduced homocysteine accumulation, indicating CRIF1 plays a key role in homocysteine metabolism.

Article Abstract

Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614757PMC
http://dx.doi.org/10.3390/antiox10111645DOI Listing

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