Deletion of p66shc gene protects against age-related endothelial dysfunction

Area of Science:

• Vascular Biology
• Aging Research
• Oxidative Stress

Background:

• Enhanced production of reactive oxygen species (ROS) is a key factor in age-related endothelial dysfunction.
• The p66shc protein regulates cellular responses to oxidative stress.
• Mice lacking p66shc exhibit increased ROS resistance and a longer lifespan.

Purpose of the Study:

• To investigate age-dependent changes in endothelial function in mice lacking the p66shc gene.
• To determine the role of p66shc in ROS-mediated endothelial dysfunction during aging.

Main Methods:

• Isometric tension recording of aortic rings from young and old p66shc-/- and wild-type (WT) mice.
• Measurement of nitric oxide (NO) release using a porphyrinic microsensor.
• Assessment of protein expression (eNOS, iNOS, superoxide dismutase) and nitrotyrosine via Western blotting and immunohistochemistry.
• Determination of superoxide (O2-) production using chemiluminescence.

Main Results:

• Endothelium-dependent relaxation and NO release were age-dependently impaired in WT mice but preserved in p66shc-/- mice.
• Old WT mice showed increased O2- production and nitrotyrosine expression compared to young WT mice.
• Aging did not affect eNOS or manganese superoxide dismutase expression, but iNOS was upregulated in old WT mice. These age-dependent changes were absent in p66shc-/- mice.

Conclusions:

• Inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction.
• The p66shc protein is involved in a signal transduction pathway crucial for endothelial integrity.
• p66shc may represent a novel therapeutic target for preventing vascular aging.