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Updated: Jul 14, 2026
Murine Model of CD40-activation of B cells
Published on: March 5, 2010
Homocysteine modulates the CD40/CD40L system
Cesaria Prontera1, Nicola Martelli, Virgilio Evangelista
1Department of Medicine, Gabriele d'Annunzio University Foundation, Chieti-Pescara, Italy.
Insights
Elevated homocysteine levels significantly increase soluble CD40L and CD40 expression, suggesting a link between hyperhomocysteinemia and cardiovascular disease risk.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Hyperhomocysteinemia (HHcy) is linked to increased atherothrombosis.
- The CD40/CD40 ligand (CD40L) dyad plays a role in vascular inflammation and atherosclerosis pathogenesis.
Purpose of the Study:
- To investigate the impact of HHcy on the CD40/CD40L dyad.
- To explore the molecular mechanisms connecting HHcy to cardiovascular disease.
Main Methods:
- Measured soluble CD40L (sCD40L) levels in HHcy patients and healthy controls using ELISA.
- Assessed CD40 and VCAM-1 expression in endothelial cells and CD40L in platelets using real-time PCR and flow cytometry after homocysteine exposure.
Main Results:
- HHcy patients exhibited significantly higher sCD40L levels.
- Homocysteine exposure increased CD40 expression in endothelial cells and CD40L expression in platelets.
- Homocysteine enhanced CD40L-induced VCAM-1 expression in endothelial cells.
Conclusions:
- The CD40/CD40L dyad is a potential molecular target of homocysteine.
- Upregulation of CD40/CD40L signaling may mediate the increased cardiovascular disease risk associated with HHcy.
Objectives:
This study evaluated the impact of hyperhomocysteinemia (HHcy) on the CD40/CD40 ligand (CD40L) dyad in vivo and in vitro.
Background:
Hyperhomocysteinemia is associated with an increased incidence of atherothrombosis, although the molecular mechanisms of this association are incompletely defined. The CD40L pair triggers inflammatory signals in cells of the vascular wall, representing a major pathogenetic pathway of atherosclerosis.
Methods:
We used a commercially available enzyme-linked immunosorbent assay kit to evaluate circulating levels of soluble (s) CD40L in 24 patients with HHcy and 24 healthy subjects. We also used real-time polymerase chain reaction and flow cytometry to determine expression levels of CD40 and vascular cell adhesion molecule (VCAM)-1 in human umbilical vein endothelial cells (HUVECs) and of CD40L in human platelets.
Results:
The sCD40L levels were significantly increased in HHcy patients (median [interquartile range] 8.0 [0.7 to 10.5] ng/ml vs. 2.1 [1.9 to 2.3] ng/ml, p = 0.0001). Positive correlations were noted between log sCD40L and log homocysteine (Hcy) (R = 0.68, p < 0.0001) or log sVCAM-1 (R = 0.41, p < 0.005). Homocysteine significantly stimulated CD40 mRNA expression in HUVECs (p = 0.033). Consistently, 24-h exposure to Hcy increased the percentage of CD40-expressing cells (p = 0.00025). Homocysteine also significantly enhanced CD40L expression in platelets (p = 0.025) to a comparable extent as that of thrombin. Notably, Hcy increased VCAM-1 protein expression induced by CD40L in HUVECs (p = 0.0046).
Conclusions:
The present results uncover a potential molecular target of Hcy, namely the CD40/CD40L dyad. Collectively, they indicate that upregulation of CD40/CD40L signaling may represent a link between HHcy and an increased risk of cardiovascular disease.
