SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Capillary Permeability*; Endothelial Cells/*pathology ; Epithelium/*pathology ; Inflammation/*metabolism ; Lung/*pathology ; Sirtuins/*deficiency; Adult ; Animals ; Bleomycin ; Cell Membrane Permeability ; Cells, Cultured ; Endothelial Cells/metabolism ; Gene Expression Regulation ; Gene Silencing ; Humans ; Inflammation Mediators/metabolism ; Lipopolysaccharides ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/pathology ; Pulmonary Fibrosis/physiopathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction ; Sirtuins/genetics ; Sirtuins/metabolism ; Transforming Growth Factor beta/metabolism

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

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0 (Inflammation Mediators)
0 (Lipopolysaccharides)
0 (NF-kappa B)
0 (RNA, Messenger)
0 (SIRT7 protein, human)
0 (Sirt7 protein, mouse)
0 (Transforming Growth Factor beta)
11056-06-7 (Bleomycin)
EC 3.5.1.- (Sirtuins)

Date Created: 20200729 Date Completed: 20201209 Latest Revision: 20210727

20240628

PMC7385158

10.1038/s41598-020-69236-z

32719338