p66(Shc)-induced redox changes drive endothelial insulin resistance

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Mitochondrial Signaling

Background:

• Obesity-induced insulin resistance (IR) is a major risk factor for cardiovascular disease (CVD).
• Endothelial insulin signaling impairment is implicated in IR, but mechanisms are unclear.
• Mitochondrial adaptor p66(Shc) promotes endothelial dysfunction through reactive oxygen species (ROS) generation.

Purpose of the Study:

• To investigate the role of p66(Shc) in obesity-related endothelial insulin signaling impairment.
• To explore p66(Shc) as a potential therapeutic target for IR and CVD.

Main Methods:

• Experiments utilized leptin-deficient (Lep(Ob/Ob)) and wild-type (WT) mice.
• In vivo gene silencing of p66(Shc) was performed.
• Endothelial cells were isolated from Lep(Ob/Ob) mice for in vitro analysis.

Main Results:

• Insulin-induced endothelium-dependent relaxations were reduced in Lep(Ob/Ob) mice compared to WT.
• p66(Shc) gene silencing in vivo restored insulin response via the IRS-1/Akt/eNOS pathway.
• p66(Shc) knockdown in endothelial cells attenuated ROS production, free fatty acid oxidation, and normalized redox-sensitive pathways.

Conclusions:

• Endothelial p66(Shc) plays a critical role in obesity-induced insulin resistance.
• Targeting endothelial p66(Shc) is a potential strategy to prevent IR and associated CVD in obesity.