Homocysteine modulates CXCL10/CXCR3 axis activity to induce endothelial dysfunction

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Biology
• Molecular Medicine

Background:

• Elevated homocysteine (Hcy) is a risk factor for cardiovascular diseases.
• Endothelial dysfunction is a key early event in atherosclerosis.
• The specific mechanisms linking Hcy to endothelial dysfunction require further elucidation.

Purpose of the Study:

• To investigate the mechanisms by which Hcy induces endothelial dysfunction.
• To examine the role of the CXCL10/CXCR3 axis in Hcy-mediated endothelial damage.
• To evaluate therapeutic strategies targeting the CXCL10/CXCR3 axis.

Main Methods:

• In vitro studies using endothelial cells exposed to Hcy.
• In vivo studies utilizing a murine model of hyperhomocysteinemia (HHcy).
• Assessment of endothelial cell functions (migration, proliferation, tube formation) and adhesion molecule expression.
• Analysis of CXCL10 and CXCR3 expression levels.
• Pharmacological blockade of the CXCL10/CXCR3 axis using antibodies and NBI-74330.

Main Results:

• Hcy significantly impairs endothelial cell migration, proliferation, and tube formation.
• Hcy upregulates adhesion molecules, contributing to endothelial dysfunction.
• In HHcy mice, elevated plasma Hcy correlates with vascular damage.
• Hcy exposure increases CXCL10 and CXCR3 expression both in vitro and in vivo.
• Blocking the CXCL10/CXCR3 axis ameliorates Hcy-induced endothelial dysfunction.

Conclusions:

• The CXCL10/CXCR3 axis is a critical mediator of Hcy-induced endothelial dysfunction.
• Targeting the CXCL10/CXCR3 pathway represents a potential therapeutic strategy for cardiovascular diseases associated with hyperhomocysteinemia.
• This study provides novel insights into the molecular mechanisms underlying Hcy-related vascular pathology.