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

Anne E Wyman,Trang T T Nguyen,Abdoulaye J Dabo,Junghyun Kim,Robert F Foronjy,Jeffrey D Hasday,Patrick Geraghty,Konstantin G Birukov,Chen-Ou Zhang,Mohan E Tulapurkar,Anna A Birukova,Sergei P Atamas,Irina G Luzina,Pratap Karki,Theresa G Feng,Nevins W Todd

doi:10.1038/s41598-020-69236-z

Abstract

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.

Highlights

SIRT7 mRNA levels were significantly lower in lung tissues from aged compared to young mice with a threefold decrease at age 18 months compared to 5 weeks (Fig. 1D)
We found significantly lower SIRT7 mRNA levels in lung tissues from aged compared to young mice and in murine lungs challenged with LPS or bleomycin
To examine cell-specific effects of SIRT7 loss in Acute lung injury (ALI), we focused our experiments on acute inflammatory responses in cultured primary pulmonary endothelial cells

Summary

Introduction

LPS, or bleomycin on mRNA levels of SIRT7 and pro-inflammatory and pro-fibrotic markers measured by RT-qPCR in mouse lung tissues. ICAM1, VCAM1, IL6, and SIRT7 mRNA levels normalized to respective β-actin mRNA levels in lung tissue samples of C57BL/6 (A) or A/J mice (B) 24 h after intranasal treatment with LPS or PBS. To gain insight into aging-related mechanisms of ALI, we investigated the relationship between SIRT7 suppression, acute inflammatory and fibrotic responses, and endothelial barrier function in LPS-induced models of ALI

Methods

Results

Conclusion