Shear stress inhibits homocysteine-induced stromal cell-derived factor-1 expression in endothelial cells

Area of Science:

• Vascular Biology
• Molecular Cardiology
• Biochemistry

Background:

• Hyperhomocysteinemia is linked to vascular dysfunction and cardiovascular disease risk.
• Stromal cell-derived factor-1 (SDF-1), a chemokine in endothelial cells (ECs), is prevalent in advanced atherosclerotic lesions.
• The interplay between homocysteine, chemokines, and shear stress in regulating endothelial function remains unclear.

Purpose of the Study:

• To investigate the mechanisms by which homocysteine and shear stress modulate EC SDF-1 expression.
• To elucidate the role of specific signaling pathways, including mitogen-activated protein kinases (MAPKs) and nitric oxide (NO), in this process.

Main Methods:

• Endothelial cells were stimulated with homocysteine and subjected to varying shear stress conditions.
• Investigated SDF-1 expression, MAPK phosphorylation (ERK, JNK, p38), and transcription factor activity (Sp1, AP-1) using inhibitors, siRNA, and dominant-negative mutants.
• Assessed the role of the nitric oxide (NO) pathway via NO donors and endothelial NO synthase (eNOS) inhibition.

Main Results:

• Homocysteine dose- and time-dependently increased SDF-1 expression and JNK phosphorylation.
• JNK pathway activation was critical for homocysteine-induced SDF-1 expression.
• Homocysteine enhanced Sp1 and AP-1 DNA binding, which were blocked by siRNA inhibition.
• Preshearing inhibited homocysteine-induced JNK phosphorylation, Sp1/AP-1 activation, and SDF-1 expression.
• NO donors suppressed homocysteine-induced SDF-1, and eNOS inhibition abolished shear stress protection.

Conclusions:

• Elucidated the molecular mechanisms of homocysteine-induced SDF-1 expression in ECs.
• Demonstrated that shear stress protects against homocysteine effects via NO signaling.
• Findings highlight the complex regulation of SDF-1 in vascular disease pathogenesis.