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Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling.

Abstract：

:BACKGROUND Microvascular endothelial inflammation and apoptosis are responsible for septic acute lung injury (ALI). Ripasudil is a novel Rho/Rho kinase (ROCK) inhibitor which shows therapeutic effects on several vascular diseases. The aim of this study was to investigate the protective effects and correlated molecular mechanisms of ripasudil on lipopolysaccharide- induced inflammation and apoptosis of pulmonary microvascular endothelial cells (PMVECs). MATERIAL AND METHODS Cultured PMVECs were exposed to lipopolysaccharide (LPS). Ripasudil at various concentrations was used to treat the cells. Several cells were also co-administrated with the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cell viability was assessed by MTT assay. Terminal dUTP transferase nick-end labeling (TUNEL) assay was used to detect the apoptosis. The colorimetric method was used to measure the activity of eNOS and ROCK2. Protein phosphorylation and expression were assessed by Western blotting. RESULTS Ripasudil attenuated the LPS-induced inflammation and apoptosis in PMVECs, which was reversed by L-NAME. Ripasudil suppressed ROCK2 activity and further increased the eNOS activity. Ripasudil treatment increased the phosphorylation of eNOS, increased the expression level of Bcl2, and decreased the expression level of active caspase3 in LPS-treated PMVECs. Moreover, the ripasudil treatment also inhibited the nuclear translocation of NF-κB and further suppressed the levels of interleukin (IL) 6 and tumor necrosis factor (TNF) α. The co-treatment with L-NAME, however, impaired the anti-apoptotic and anti-inflammatory effects of ripasudil on PMVECs without affecting ROCK2. CONCLUSIONS The novel ROCK2 inhibitor ripasudil suppressed LPS-induced apoptosis and inflammation in PMVECs by regulating the ROCK2/eNOS signaling pathway.

journal_name

Med Sci Monit

journal_title

Medical science monitor : international medical journal of experimental and clinical research

authors

Yang J,Ruan F,Zheng Z

doi

10.12659/MSM.910184

subject

Has Abstract

pub_date

2018-05-16 00:00:00

pages

3212-3219

eissn

1234-1010

issn

1643-3750

pii

910184

journal_volume

pub_type

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Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling.