Abstract
Epigenetic regulation involves histone methylation and the methylation state of these DNA binding proteins is dependent on histone methyl-transferases but also by demethylases. Histone H3 is one of the most frequently modified histones. Methylation at H3-lysine-4 (H3K4me3) is located in promoter region, increases gene expression whereas removal of this histone mark silences transcription. We hypothesized that a low H3K4 methylation state is involved in the maintenance of a normal quiescent endothelial phenotype. To identify factors controlling H3K4 methylation in human umbilical vein endothelial cells (HUVECs), H3K4 demethylases were screened. As a highly expressed H3K4 demethyase, Jarid1b was identified by PCR and Western blot analysis. To uncover potential functions of Jarid1b, RNAi experiments were performed. Knockdown of Jarid1b by shRNA in HUVECs attenuated angiogenic sprouting, tube formation and cell migration in the scratch wound assay. Importantly, also 2-4(4-methylphenyl)-1,2-benzisothiazol-3-(2H)-one, a pharmacological Jarid1b inhibitor, diminished the angiogenic capacity of endothelial cells. To clarify the importance of Jarid1b function in the vascular system, Jarid1b knockout mice were studied. As global knockout of the gene is embryonic lethal, tamoxifen-inducible conditional knockout mice were generated. After knockout of Jarid1b, endothelial sprout outgrowth from aortic segments was attenuated. Moreover, Jarid1b diminished the acetylcholine-induced endothelium-dependent relaxation whereas the SNP-induced endothelium-independent relaxation was not affected. As basal NO release was not altered by Jarid1b knockout, alterations in the muscarinic receptor pathway were analyzed. Exon-array technique indeed revealed that Jarid1b maintains cholineric receptor mRNA level. Conclusion: Jarid1b maintains endothelial angiogenic capacity in part by controlling endothelial cell receptor expression.
Original language | English |
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Journal | Clinical Research in Cardiology |
Volume | 103 |
Issue number | Suppl 1 |
ISSN | 1861-0684 |
DOIs | |
Publication status | Published - Apr 2014 |
Externally published | Yes |
Event | 80. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung - Mannheim, Germany Duration: 23 Apr 2014 → 26 Apr 2014 |
Conference
Conference | 80. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung |
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Country/Territory | Germany |
City | Mannheim |
Period | 23/04/2014 → 26/04/2014 |