Flow shear force destabilizes carotid plaques by affecting CHOP and GRP78 proteins

Area of Science:

• Cardiovascular Research
• Biomedical Engineering
• Molecular Biology

Background:

• Ischemic stroke is often caused by unstable carotid atherosclerotic plaque, with 18-25% linked to plaque rupture.
• Plaque stability is critical for patient prognosis, necessitating accurate methods to assess it.
• Previous studies linked CHOP (C/EBP homologous protein) and GRP78 (glucose-regulated protein 78) expression to plaque stability.

Purpose of the Study:

• To investigate the impact of blood flow shear force on GRP78 and CHOP expression in endothelial cells.
• To empirically study how shear force affects the stability of human carotid atherosclerotic plaques.
• To explore the role of hemodynamic factors in carotid plaque instability.

Main Methods:

• Human umbilical vein endothelial cells were exposed to low, medium, and high shear forces (4, 8, 12 dynes/cm²).
• GRP78 and CHOP protein and mRNA levels were quantified using Western blot and RT-qPCR.
• Plaques from 60 patients were classified as stable or unstable, with shear force measured at the carotid bifurcation.

Main Results:

• Low shear force significantly elevated GRP78 and CHOP expression in endothelial cells compared to medium and high shear.
• Unstable carotid plaques exhibited significantly lower shear forces at the bifurcation than stable plaques.
• GRP78 and CHOP expression levels were significantly higher in unstable plaques compared to stable ones.

Conclusions:

• Blood flow shear forces differentially regulate GRP78 and CHOP expression in vascular endothelial cells.
• Reduced shear force and lower fluid flow rates correlate with increased GRP78 and CHOP expression.
• Elevated GRP78 and CHOP may induce endoplasmic reticulum stress, contributing to carotid plaque destabilization and stroke risk.