Post-Transcriptional Regulation of Hepatic DDAH1 with TNF Blockade Leads to Improved eNOS Function and Reduced Portal...

Area of Science:

• Hepatology
• Vascular Biology
• Immunology

Background:

• Portal hypertension (PH) is a significant complication of chronic liver disease, linked to inflammation and pro-inflammatory cytokines like TNF.
• Tumor necrosis factor (TNF) and NFkB are elevated in bile duct ligation (BDL) induced PH models.
• Vascular tone dysregulation contributes to the pathophysiology of PH.

Purpose of the Study:

• To investigate the therapeutic potential of Infliximab (IFX), a TNF inhibitor, in a rat model of PH.
• To assess the impact of IFX on vascular tone modulation, inflammation, and oxidative stress in PH.
• To explore the role of the DDAH1/ADMA axis in the context of inflammation and oxidative stress in PH.

Main Methods:

• Utilized a bile duct ligation (BDL) rat model to induce PH.
• Administered Infliximab (IFX) to BDL rats and assessed its effects on portal pressure, TNF, NFkB, oxidative stress, and liver injury markers.
• Evaluated endothelial nitric oxide synthase (eNOS) activity, L-arginine/ADMA ratio, and DDAH1 expression.
• Conducted in vitro studies on HepG2 hepatocytes to investigate DDAH1 regulation by oxidative stress.

Main Results:

• IFX treatment significantly reduced portal pressure in BDL rats, accompanied by decreased TNF and NFkB levels.
• IFX administration attenuated hepatic oxidative stress, inflammation, and injury markers.
• IFX improved eNOS activity, increased the L-arginine/ADMA ratio, and upregulated DDAH1 expression.
• In vitro, oxidative stress reduced DDAH1 protein expression in HepG2 cells, partly via 3'UTR-mediated post-transcriptional regulation.

Conclusions:

• IFX effectively reduces portal pressure and ameliorates liver injury in a rat model of PH by inhibiting TNF.
• The DDAH1/ADMA axis plays a crucial role in mediating the effects of inflammation and oxidative stress in PH.
• Targeting the DDAH1/ADMA pathway presents a promising therapeutic strategy for managing PH.