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Homocysteine accelerates senescence of endothelial cells via DNA hypomethylation of human telomerase reverse transcriptase.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2015 Jan; Vol. 35 (1), pp. 71-8. Date of Electronic Publication: 2014 Oct 30. - Publication Year :
- 2015
-
Abstract
- Objective: Homocysteine can accelerate the senescence of endothelial progenitor cells or endothelial cells (ECs) via telomerase inactivation and length shortening. However, the underlying mechanism is unclear. Here, we investigated whether homocysteine promotes endothelial senescence by reducing the expression and activity of human telomerase reverse transcriptase (hTERT) by DNA methylation to reduce ECs telomerase activity.<br />Approach and Results: When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages. Interestingly, homocysteine-stimulated but not angiotensin II-stimulated ECs senescence could be reversed by hypermethylation induced by folic acid or s-adenosylmethionine supplementation. Meanwhile, homocysteine promoted the shortening of telomere length specifically related to restoration of hTERT transcriptional expression and CCCTC-binding factor binding sites with hTERT promoter hypomethylation, as detected by quantitative real-time polymerase chain reaction, Western blot, methylation-specific polymerase chain reaction, and bisulfite sequencing assay. Electrophoretic mobility shift assay and chromatin immunoprecipitation results showed that homocysteine-reduced telomere activity and homocysteine-induced EC senescence might contribute to hTERT promoter demethylation by increasing CCCTC-binding factor repression and interfering in the SP1 binding to the demethylated hTERT promoter, which might relate with reduced of DNA methyltransferase 1. Furthermore, the CCCTC-binding factor-dependent mechanism of homocysteine-reduced hTERT expression via DNA demethylation was confirmed in aortic endothelia of mice with hyperhomocysteine levels.<br />Conclusions: CCCTC-binding factor and SP1 cross talk may contribute to homocysteine-reduced hTERT DNA methylation and expression in endothelial senescence.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Angiotensin II metabolism
Animals
Binding Sites
CCCTC-Binding Factor
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Disease Models, Animal
Folic Acid pharmacology
Gene Expression Regulation, Enzymologic
Human Umbilical Vein Endothelial Cells enzymology
Humans
Hyperhomocysteinemia blood
Hyperhomocysteinemia enzymology
Hyperhomocysteinemia genetics
Male
Mice, Inbred C57BL
Promoter Regions, Genetic
RNA Interference
Repressor Proteins genetics
Repressor Proteins metabolism
S-Adenosylmethionine pharmacology
Sp1 Transcription Factor genetics
Sp1 Transcription Factor metabolism
Telomerase genetics
Telomere metabolism
Telomere Shortening drug effects
Time Factors
Transfection
Tumor Suppressor Protein p53 metabolism
Cellular Senescence drug effects
DNA Methylation drug effects
Homocysteine pharmacology
Human Umbilical Vein Endothelial Cells drug effects
Telomerase metabolism
Telomere drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 35
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 25359865
- Full Text :
- https://doi.org/10.1161/ATVBAHA.114.303899