EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK...

Area of Science:

• Vascular Biology
• Pulmonary Medicine
• Pharmacology

Background:

• Endothelial barrier integrity is critical for sepsis prognosis.
• Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with known protective effects.
• The role of EETs in endothelial barrier enhancement and their mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of EETs in enhancing endothelial barrier function.
• To elucidate the mechanisms by which EETs regulate vascular permeability.
• To explore therapeutic potential for sepsis-induced lung injury.

Main Methods:

• Overexpression of endothelial cytochrome P450 epoxygenase 2J2 (CYP2J2) and administration of soluble epoxide hydrolase (sEH) inhibitors (TPPU, AUDA) in vivo and in vitro models.
• Lipopolysaccharide (LPS)-induced sepsis model in mice.
• Assessment of endothelial hyper-permeability, survival rates, GRP78-Src interaction, reactive oxygen species (ROS) production, RhoA/ROCK activation, and phosphorylation of VE-cadherin and myosin light chain (MLC).

Main Results:

• Increased EETs levels via CYP2J2 overexpression or sEH inhibition reduced LPS-induced endothelial hyper-permeability and improved survival in septic mice.
• sEH inhibitor AUDA and 11,12-EET decreased endothelial hyper-permeability in vitro.
• Mechanisms involved reduced GRP78-Src interaction and ROS production, leading to decreased RhoA/ROCK activation and phosphorylation of VE-cadherin and MLC.

Conclusions:

• CYP2J2-derived EETs are crucial for regulating vascular permeability through RhoA-dependent cytoskeletal changes.
• EETs represent a promising therapeutic target for pulmonary edema and other diseases associated with abnormal vascular permeability.