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Papers of the Week

2020 Jun 03

Pflugers Arch

Sirtuin 1 and endothelial glycocalyx.


Lipphardt M, Song J W, Goligorsky MS
Pflugers Arch. 2020 Jun 03.
PMID: 32494847.


Sirtuin1 deficiency or reduced activity comprises one of the hallmarks of diseases as diverse as chronic cardiovascular, renal, and metabolic, some malignancies, and infections, as well as aging-associated diseases. In a mouse model of endothelium-limited defect in sirtuin 1 deacetylase activity, we found a dramatic reduction in the volume of endothelial glycocalyx. This was associated with the surge in the levels of one of key scaffolding heparan sulfate proteoglycans of endothelial glycocalyx, syndecan-4, and specifically, its extracellular domain (ectodomain). We found that the defect in endothelial sirtuin 1 deacetylase activity is associated with (a) elevated basal and stimulated levels of superoxide generation (via the FoxO1 over-acetylation mechanism) and (b) increased nuclear translocation of NF-kB (via p65 over-acetylation mechanism). These findings laid the foundation for the proposed novel function of sirtuin 1, namely, the maintenance of endothelial glycocalyx, particularly manifest in conditions associated with sirtuin 1 depletion. In the forthcoming review, we summarize the emerging conceptual framework of the enhanced glycocalyx degradation in the states of defective endothelial sirtuin 1 function, thus explaining a broad footprint of the syndrome of endothelial dysfunction, from impaired flow-induced nitric oxide production, deterrent leukocytes infiltration, increased endothelial permeability, coagulation, and pro-inflammatory changes to development of microvascular rarefaction and progression of an underlying disease.