Hearts & minds… also mustn’t forget about those kidneys #CovidPapers #endothelialDamage #VascularInflammation #dementia #alzheimers #CKD
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https://academic.oup.com/ehjcimaging/advance-article-abstract/doi/10.1093/ehjci/jead118/7186983
https://www.nature.com/articles/s44161-023-00336-5
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https://www.biorxiv.org/content/10.1101/2023.09.01.555834v1
MRTF-A as a deacetylation target of Sirt6 in #EndothelialCell
Deactylated MRTF-A stays in cytoplasm, failing to mediate oxLDL-induced EC ICAM1
An OxLDL-DNMT1 cacade epigenetically silences Sirt6 expression
Dr. Qianyun Wang, Tianfa Li & Qianwen Zhao labs Cell Death Discov 2022
https://www.nature.com/articles/s41420-022-00903-y
Oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis, activates the transcription of adhesion molecules (ICAM-1) in endothelial cells. We previously showed that myocardin-related transcription factor A (MRTF-A) mediates oxLDL-induced ICAM-1 transcription. Here we confirm that ICAM-1 transactivation paralleled dynamic alterations in MRTF-A acetylation. Since treatment with the antioxidant NAC dampened MRTF-A acetylation, MRTF-A acetylation appeared to be sensitive to cellular redox status. Of interest, silencing of SIRT6, a lysine deacetylase, restored MRTF-A acetylation despite the addition of NAC. SIRT6 directly interacted with MRTF-A to modulate MRTF-A acetylation. Deacetylation of MRTF-A by SIRT6 led to its nuclear expulsion thus dampening MRTF-A occupancy on the ICAM-1 promoter. Moreover, SIRT6 expression was downregulated with oxLDL stimulation likely owing to promoter hypermethylation in endothelial cells. DNA methyltransferase 1 (DNMT1) was recruited to the SIRT6 promoter and mediated SIRT6 repression. The ability of DNMT1 to repress SIRT6 promoter partly was dependent on ROS-sensitive serine 154 phosphorylation. In conclusion, our data unveil a novel DNMT1-SIRT6 axis that contributes to the regulation of MRTF-A acetylation and ICAM-1 transactivation in endothelial cells.
Matt Willemsen
Lorraine
Hao Yin