eNOS S-nitrosylation mediated OxLDL-induced endothelial dysfunction via increasing the interaction of eNOS with...

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Biology
• Molecular Medicine

Background:

• Protein S-nitrosylation is implicated in cardiovascular disease progression.
• Endothelial nitric oxide synthase (eNOS) S-nitrosylation attenuates its activity and interacts with beta-catenin.
• The role of eNOS S-nitrosylation in regulating the beta-catenin pathway and endothelial dysfunction is unclear.

Purpose of the Study:

• To investigate how eNOS S-nitrosylation regulates the beta-catenin signal pathway and contributes to endothelial dysfunction.
• To elucidate the specific mechanisms and molecular players involved in OxLDL-induced endothelial injury.

Main Methods:

• Utilized endothelial cells treated with oxidized low-density lipoprotein (OxLDL).
• Investigated eNOS S-nitrosylation, its interaction with beta-catenin, and beta-catenin transcriptional activity.
• Employed site-directed mutagenesis of eNOS (Cys94, Cys99, Cys441) and utilized an iNOS inhibitor (1400W).

Main Results:

• OxLDL induces eNOS S-nitrosylation, enhancing eNOS-beta-catenin interaction, beta-catenin activity, cell migration, and adhesion molecule expression.
• Mutations at eNOS Cys94 and Cys99, but not Cys441, partially abolished these OxLDL-induced effects.
• OxLDL increased iNOS expression; iNOS inhibition reduced eNOS S-nitrosylation and beta-catenin pathway activation, alleviating endothelial dysfunction.

Conclusions:

• OxLDL induces eNOS S-nitrosylation at Cys94 and Cys99 in an iNOS-dependent manner.
• This S-nitrosylation enhances beta-catenin activation, contributing to OxLDL-induced endothelial dysfunction.
• Identified a novel mechanism underlying endothelial injury in cardiovascular diseases.