p21(Waf1/Cip1/Sdi1) mediates shear stress-dependent antiapoptotic function

Area of Science:

• Endothelial cell biology
• Molecular mechanisms of apoptosis
• Cardiovascular research

Background:

• Endothelial cells are crucial for vascular health.
• Apoptosis, or programmed cell death, contributes to vascular dysfunction.
• The role of p21 (Waf1/Cip1/Sdi1) in endothelial cell survival under stress is not fully understood.

Purpose of the Study:

• To investigate the antiapoptotic role of p21 in human umbilical vein endothelial cells (HUVEC) under shear stress (SS) and nitric oxide (NO) stimulation.
• To evaluate the efficacy of p21 gene transfer in preventing apoptosis in a mouse model of hindlimb ischemia.

Main Methods:

• In vitro: HUVEC were subjected to simulated hypoxia, shear stress, or treated with sodium nitroprusside (SNP), a nitric oxide donor. p21 expression was modulated using recombinant adenoviruses.
• In vivo: A mouse model of hindlimb ischemia was established by femoral artery ligation. SNP was administered, and p21 gene transfer was performed via direct injection.

Main Results:

• Both shear stress and SNP treatment increased p21 levels and reduced apoptosis in HUVEC.
• Overexpression of p21 protected HUVEC from apoptosis, while its inhibition sensitized cells to death.
• In ischemic hindlimbs, SNP treatment enhanced p21 expression and reduced tissue damage.
• Direct in vivo gene transfer of p21 significantly decreased apoptotic nuclei in ischemic tissues.

Conclusions:

• p21 plays a significant role in the antiapoptotic effects of shear stress and nitric oxide in endothelial cells.
• p21 gene transfer is a promising strategy to prevent apoptosis in conditions of acute blood flow interruption.